Oral pharmaceutical composition

ABSTRACT

An oral composition comprising minicapsules wherein the minicapsules comprise one or more therapeutic or prophylactic substances in a liquid, semi-liquid, or solid core. The minicapsules have release profiles to release the substance in an active form at one or more sites along the gastro-intestinal tract to maximize absorption and/or therapeutic efficiency.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of Ser. No. 12/594,542, filed on May26, 2010, which is the U.S. National Stage of International ApplicationNo. PCT/IE2008/000040, filed Apr. 4, 2008, which was published inEnglish under PCT Article 21(2), which in turn claims the benefit ofU.S. Provisional Application No. 60/907,490, filed Apr. 4, 2207, andU.S. Provisional Application No. 61/006,498, filed Jan. 16, 2008. Theprovisional applications are incorporated herein in their entirety.

The present invention relates to multiple minicapsule or minispheremodified release compositions.

INTRODUCTION

A fundamental principle that underlies pharmaco-therapeutic interventionis the need for a drug molecule to interact with its specific receptor.Addressing this need, pharmaceutical formulation technology hasdeveloped methods to enhance the solubility of drugs and to maintainsolubilised drug molecules as single molecular entities.

The contents and medium in the gastro-intestinal tract (GIT) isprimarily aqueous in nature. The solubility of drugs in the GIT isdependent on their physicochemical properties and is affected by the pH,bile salts, bacteria, water content, amongst other factors. Generally,depending on the local pH, water-soluble or hydrophilic drugs arereadily soluble throughout the GIT whereas poorly water-solublehydrophobic or lipophilic drugs are insoluble or have limited solubilityin the GIT.

Various technologies have been developed to address enhancing thesolubility of hydrophobic and lipophilic drugs. Further technologieshave been developed to enhance or maintain the solubility of pHsensitive drugs to prevent precipitation in acid, neutral or basicenvironments.

Utilising traditional oral drug delivery technologies, colonic deliveryhas proven difficult, in particular for small molecule drugs withlimited water solubility. This difficulty stems from the preference ofhydrophobic or lipophilic drugs to aggregate in an aqueous environment.There, therefore, exists a need for a technology which will enablesolubility equalisation of hydrophilic, hydrophobic or lipophilic drugswhen released from an orally administered format regardless of wherealong the GIT the drug is released, including in the colon.

Controlled release formulations have been suited mainly to water-solubledrugs that conform with conventional pill or pellet forms and whenreleased from such formats are readily soluble in the aqueous GITenvironment. However, conventional forms have not facilitatedhydrophobic or lipophilic drugs that are optimally formulated asnon-powders, such as those that are formulated as various lipid-based orother solubility enhancing excipient-based liquid, semi-solid or solidformats. A technology to enable any compound to be released into anyregion of the GIT in a soluble form is desirable.

Lipid-based formulations have been developed to enhance the solubilityof non-water soluble compounds and invariably take an oil, emulsion, asuspension, a waxy form, a colloid, liposome, or other non-powder orsolid form. Additionally, lipid-based formulations have been utilized toenhance the permeability of compounds, including hydrophilic compounds,which do not pass readily from the intestine into the bloodstream. Suchlipid based formulations have been administered to subjects as largesoft-gel capsules. As large soft-gel capsules are soft and pliable andhave a seam, they are unsuited to further processing, including coatingwith controlled release polymers. Even if such formats could beuniformly and effectively coated, once the controlled release coating isbreached, the entire contents of the capsule would be released in abolus-like effect. Without coating, the drug is released into thestomach in a quantity that may be above the therapeutic index and thusresult in long term toxic side effects. The development of a controlledrelease technology to overcome the issues associated with the limitinglarge soft-gel capsule form is therefore desirable.

Another issue associated with many drugs relates to the fact that theyare absorbed with different efficiencies as they pass from the smallintestine through to the colon. In some instances, a poorlywater-soluble drug formulated either in a lipid-based non-powder or anenhanced solubility powder form demonstrates absorption in the smallintestine but not in the colon. In some instances, apart from enhancingsolubility some lipid based formulations, such as various emulsion-basedformulations also enhance intestinal absorption, of both water-solubleand poorly water-soluble drugs, through enhancing interaction with bilesalts and other endogenous emulsifiers to form drug micelles which aremore readily absorbed, mainly in the upper small intestine.

In general, pH-dependent systems for targeting a pharmaceutical activerelease to a specific location in the intestine can be unreliable for anumber of reasons. For example, premature release and associatedsystemic absorption of the parent compound may result from a proximalintestinal pH at or above the critical triggering pH. Alternatively,incomplete or minimal release may result from the occurrence of thecritical pH at a site distal of the affected area. Nugent et al, Gut 48,pages 571-577 (2001), reviews the potential problems of the pH-dependentdistal gut delivery approach, pointing out that the existence ofinter-subject variations in intestinal pH.

U.S. Pat. No. 5,716,648 describes an oral composition that relies on apH-dependent soluble coating, but also includes a pH-regulating alkalinematerial to attempt to compensate for patients with “subnormalintestinal pH.” Other approaches include those described in U.S. Pat.No. 5,866,619, which is generally directed to a non-pH-dependent colonicdrug-delivery system involving a saccharide-containing polymer, which isenzymatically degraded by the colon. Another example is provided by U.S.Pat. No. 6,506,407, which generally describes a colon-specificdrug-releasing system that combines a pH-dependent outer coating withthe inclusion of a saccharide substrate, which upon enzymatic breakdownby enterobacteria produces an organic acid that subsequently dissolvesan acid-soluble inner coating.

Still other examples are described in U.S. Application No. 2002/0098235,which describes the use of multiple pH-dependent coatings to reduce theimpact of coating fractures. U.S. Application No. 2001/0055616 describesa pellet formulation for treating intestinal tract conditions, whichutilizes a pH-dependent enteric coating to target release from anon-gel-forming drug-containing polymeric matrix core. U.S. Application2001/0036473 describes a pH-dependent coating on ahydroxypropylmethylcellulose capsule for enteric and colonic delivery.U.S. Application No. 2001/0026807 describes various coatings, includingpH-dependent materials, redox-sensitive materials, and materials subjectto breakdown by bacteria, on a starch capsule to achieve colonicdelivery.

The various strategies for targeting orally administered drugs to thecolon include covalent linkage of a drug with a carrier, including thosethat enhance stability as well as perhaps increase hydrophilicity;coating with pH-sensitive polymers; formulation of timed releasedsystems, exploitation of carriers that are degraded specifically bycolonic bacteria; bioadhesive systems; and osmotic controlled drugdelivery systems. Various prodrugs (sulfasalazine, ipsalazine,balsalazine and olsalazine) have been developed that are aimed todeliver 5-amino salicylic acid (5-ASA) for localized chemotherapy ofinflammatory bowl disease (IBD). Microbially degradable polymersespecially azo crosslinked polymers have been investigated for use intargeting of drugs to colon. Certain plant polysaccharides such asamylose, inulin, pectin and guar gum remains unaffected in the presenceof gastrointestinal enzymes and pave the way for the formulation ofcolon targeted drug delivery systems. Additionally, combinations ofplant polysaccharides with crustacean extract, including chitosan orderivatives thereof, are proving of interest for the development ofcolonic delivery systems.

The concept of using pH as a trigger to release a drug in the colon isbased on the pH conditions that vary continuously down thegastrointestinal tract. Time-dependent drug delivery systems have beendeveloped that are based on the principle to prevent release of druguntil 3-4 h after leaving the stomach. Redox sensitive polymers andbioadhesive systems have also been exploited to deliver the drugs intothe colon.

The pH-dependent systems exploit the generally accepted view that pH ofthe human GIT increases progressively from the stomach (pH 1-2 whichincreases to 4 during digestion), small intestine (pH 6-7) at the siteof digestion and it increases to 7-8 in the distal ileum. The coating ofpH-sensitive polymers to the tablets, capsules or pellets providedelayed release and protect the active drug from gastric fluid. Thepolymers used for colon targeting, however, should be able to withstandthe lower pH values of the stomach and of the proximal part of the smallintestine and also be able to disintegrate at the neutral of slightlyalkaline pH of the terminal ileum and preferably at the ileocecaljunction.

Lorenzo-Lamosa et al. (Design of microencapsulated chitosan microspheresfor colonic drug delivery. J Control Rel, 52: 109-118, 1998) preparedand demonstrated the efficacy of a system, which combines specificbiodegradability and pH dependent release behaviour. The system consistsof chitosan microcores entrapped within acrylic microspheres containingdiclofenac sodium as model drug. The drug was efficiently entrappedwithin the chitosan microcores using spray drying and thenmicroencapsulated into Eudragit™ L-100 and Eudragit™ S-100 using anoil-in-oil solvent evaporation method. Release of the drug from chitosanmultireservoir system was adjusted by changing the chitosan molecularweight or the type of chitosan salt. Furthermore, by coating thechitosan microcores with Eudragit™, perfect pH-dependent releaseprofiles were attained. Similarly, melt extrusion of a drug with variousEudragit polymers in the presence or absence of chitosan, gelling agentsor the like has the potential to enable colon-specific release.

Polysaccharides, the polymer of monosaccharides retains their integritybecause they are resistant to the digestive action of gastrointestinalenzymes. The matrices of polysaccharides are assumed to remain intact inthe physiological environment of stomach and small intestine but oncethey reach in the colon, they are acted upon by the bacterialpolysaccharidases and results in the degradation of the matrices. Thisfamily of natural polymers has an appeal to the area of drug delivery asit is comprised of polymers with a large number of derivatizable groups,a wide range of molecular weights, varying chemical compositions, andfor the most part, a low toxicity and biodegradability, yet a highstability. The most favourable property of these materials is that theyare already approved as pharmaceutical excipients. A large number ofpolysaccharides such as amylose, guar gum, pectin, chitosan, inulin,cyclodextrins, chondroitin sulphate, dextrans and locust bean gum aswell as modifications thereof have been investigated for their use incolon targeted drug delivery systems. The most important fact in thedevelopment of polysaccharide derivatives for colon targeted drugdelivery is the selection of a suitable biodegradable polysaccharide. Asthese polysaccharides are usually soluble in water, they must be madewater insoluble by crosslinking or hydrophobic derivatisation.

Guar gum is hydrophilic in nature and swells in cold water formingviscous colloidal dispersions or sols. This gelling property retardsrelease of the drug from the dosage form as well as it is susceptible todegradation in the colonic environment. Homogenized and diluted fecesfrom human source were incubated with the guar gum to investigate thedegradation of polysaccharide by intestinal microflora. It produced arapid decrease in viscosity and fall in pH while no such results wereobserved when it was incubated with autoclaved fecal homogenates. Guargum was crosslinked with increasing amounts of trisodiumtrimetaphosphate to reduce its swelling properties for use as a vehiclein oral delivery formulations. As a result of the crosslinking procedureguar gum lost its non-ionic nature and became negatively charged. Thiswas demonstrated by methylene blue adsorption studies and swellingstudies in sodium chloride solutions with increasing concentrations inwhich the hydrogels' network collapsed (Gliko-Kabir, I., Yagen, B.,Penhasi, A. and Rubinstein, A., Phosphated crosslinked guar forcolon-specific drug delivery. I. Preparation and physicochemicalcharacterization. J Control Rel, 63: 121-127, 2000). Crosslinked guargum products were analysed to check the efficacy as colon-specific drugcarrier and it was found that the product which was crosslinked with 0.1molar equivalent of trisodium trimetaphosphate was able to prevent therelease of 80% of its hydrocortisone load for at least 6 h in PBS (pH6.4). When a mixture of α-galactosidase and β-mannanase was added to thebuffer solution, an enhanced release was observed. In vivo degradationstudies in the rat caecum showed that despite the chemical modificationof guar gum, it retained its enzyme-degrading properties in acrosslinker concentration dependent manner. A novel tablet formulationfor oral administration using guar gum as the carrier and indomethacinas a model drug has been investigated for colon targeted drug deliveryusing in vitro methods. Drug release studies under conditions simulatingthe gastrointestinal transit have shown that guar gum protects the drugfrom being released completely in the physiological environment ofstomach and small intestine. Studies in pH 6.8 PBS containing rat caecalcontents have demonstrated the susceptibility of guar gum to the colonicbacterial enzyme action with consequent drug release (Rama Prasad, Y.V., Krishnaiah, Y. S. R. and Satyanarayana, S., In vitro evaluation ofguar gum as a carrier for colon-specific drug delivery. J Control Rel,51: 281-287, 1998).

Colon-specific drug delivery may be possible by the application of driedamylose films to pharmaceutical formulations. Amylose, one of the majorfractions of starch, possesses the ability to form films throughgelation, when prepared under appropriate conditions. The microstructureof the film is potentially resistant to the action of pancreaticα-amylase but is digested by amylases of the colonic microflora.However, under simulated gastrointestinal conditions, coatings madesolely of amylose will become porous and allow drug release.Incorporation of insoluble polymers into the amylose film, to controlamylose swelling, provides a solution to this problem. A range ofcellulose and acrylate based copolymers were assessed, of which acommercially available ethylcellulose (Ethocel) was found to control theswelling most effectively. The in vitro dissolution of various coatedpellets under simulated gastric and small intestinal conditions, usingcommercially available pepsin and pancreatin was determined anddemonstrated the resistance of the amylose-Ethocel coat (1:4) to suchconditions over a period of 12 h (Milojevic, S., Newton, J. M.,Cummings, J. H., Gibson, G. R., Botham, R. L., Ring, S. C., Stockham, M.and Allwood, M. C., Amylose as a coating for drug delivery the colon:Preparation and in vitro evaluation using 5-aminosalicylic acid pellets.J Control Rel, 38: 75-84, 1996).

Chitosan is a high molecular weight polycationic polysaccharide derivedfrom naturally occurring chitin by alkaline deacetylation. Chitosan hasfavourable biological properties such as nontoxicity, biocompatibilityand biodegradability. Similar to other polysaccharides it also undergoesdegradation by the action of colonic microflora and hence poses itscandidature for colon targeted drug delivery. Tozaki et al. (Tozaki, H.,Odoriba, T., Okada, N., Fujita, T., Terabe, A., Suzuki, T., Okabe, S.,Murnishi, S. and Yamamoto, A., Chitosan capsules for colon-specific drugdelivery: enhanced localization of 5-aminosalicylic acid in the largeintestine accelerates healing of TNBS-induced colitis in rats. J ControlRel, 82, 51-61, 2002) developed colon-specific insulin delivery withchitosan capsules. In vitro drug release experiments from chitosancapsules containing 5(6)-carboxyfluorescein (CF) were carried out byrotating basket method with slight modifications. The intestinalabsorption of insulin was evaluated by measuring the plasma insulinlevels and its hypoglycaemic effects after oral administration of thechitosan capsules containing insulin and additives. Little release of CFfrom the capsules was observed in an artificial gastric juice (pH 1), orin an artificial intestinal juice (pH 7). However, the release of CF wasmarkedly increased in the presence of rat caecal contents. This groupfurther evaluated colon-specific insulin delivery using chitosancapsules. It was found that these were stable in the stomach and smallintestine but degraded by micro-organism in rat caecal contents uponentering into the colon proving their utility as carriers for colontargeted drug delivery of peptide and non-peptide drugs.

Pectin, a predominately linear polymer of mainly α-(1→4)-linkedD-polygalacturonic acid residues, has been widely investigated as acolon-specific drug delivery entity. It can be broken down by pectinaseenzymes produced by anaerobic bacteria of the colon and can control drugrelease by this principle (Atyabi et al, Carbohyd. Polymers, 2005, 61,39-51). As pectin is water soluble, efficient colonic delivery requiresthat the solubility is controlled. Liu et al. (Liu et al, Biomaterials2003, 24, 3333-3343) demonstrated promising drug delivery potential whenpectin was combined with water-insoluble polymers. Previously, Wakerlyet al. (Wakerly et al., Pharm. Res., 1996, 13 (8), 1210-1212) identifiedthat a combination of ethylcellulose and pectin could provide protectionof a drug in the upper GI tract while allowing enzymatic breakdown anddrug release in the colon. Wei et al. (Wei et al., PDA Journal ofPharmaceutical Science and Technology, Vol 61, No. 2, March-April 2007,121-130) demonstrated that colon-specific controlled release of thewater-soluble anticancer agent, 5-fluorouracil, was possible whenincorporated into pellets that were coated with various proportions ofpectin and ethycellulose (Surlease®).

Redox potential is an expression of the total metabolic and bacterialactivity in the colon and it is believed to be insensitive to dietarychanges. The mean redox potential in proximal small bowel is −67±90 my,in the distal small bowel is −196±97 my and in the colon is −145±72 my.Thus, microflora-induced changes in the redox potential can be used as ahighly selective mechanism for targeting to the colon. Bragger et al.(Investigations into the azo reducing activity of a common colonicmicroorganism. Int J Pharm, 157: 61-71, 1997) carried out investigationsinto the azo reducing activity, which could enlighten some factorsaffecting the bacterial reduction (cleavage) of azo compounds. A commoncolonic bacterium, Bacteroides fragilis was used as test organism andthe reduction of azo dyes amaranth, Orange II, tartrazine and a modelazo compound, 4,4′-dihydroxyazobenzene were studied. It was found thatthe azo compounds were reduced at different rates and the rate ofreduction could be correlated with the redox potential of the azocompounds. Disulphide compounds can also undergo degradation due to theinfluence of redox potential in the colon. Noncrosslinkedredox-sensitive polymers containing an azo and/or a disulfide linkage inthe backbone have been synthesised (Schacht, E. and Wilding, I. R.,Process for the preparation of azo- and/or disulfide-containingpolymers. Patent: WO 9111175).

Controlled Release Polymers—Membrane-Controlled Dosage Forms

The GI residence time of the dosage forms is another important parameterfor pH-dependent colon targeted drug delivery systems which isinfluenced by many physiological and other factors; nevertheless, thereare some generally accepted GI residence values for various parts of theGIT. Most commonly used pH-dependent coating polymers are methacrylicacid copolymers, commonly known as Eudragit™ (Registered trademark ofEvonik AG, Darmstadt, Germany). EUDRAGIT™ polymers (available fromEvonik) are polymeric lacquer substances based on acrylates and/ormethacrylates. A suitable polymer that is freely permeable to the activeingredient and water is EUDRAGIT™ RL. A suitable polymer that isslightly permeable to the active ingredient and water is EUDRAGIT™ RS.Other suitable polymers that are slightly permeable to the activeingredient and water, and exhibit a pH-dependent permeability include,but are not limited to, EUDRAGIT™ L, EUDRAGIT™ S, and EUDRAGIT™ E.

EUDRAGIT™ RL and RS are acrylic resins comprising copolymers of acrylicand methacrylic acid esters with a low content of quaternary ammoniumgroups. The ammonium groups are present as salts and give rise to thepermeability of the lacquer films. EUDRAGIT™ RL and RS are freelypermeable (RL) and slightly permeable (RS), respectively, independent ofpH. The polymers swell in water and digestive juices, in apH-independent manner. In the swollen state, they are permeable to waterand to dissolved active compounds.

EUDRAGIT™ L is an anionic polymer synthesized from methacrylic acid andmethacrylic acid methyl ester. It is insoluble in acids and pure water.It becomes soluble in neutral to weakly alkaline conditions. Thepermeability of EUDRAGIT™ L is pH dependent. Above pH 5.0, the polymerbecomes increasingly permeable.

Eudragit™ L100 and S100 are copolymers of methacrylic acid and methylmethacrylate. The ratio of carboxyl to ester groups is approximately 1:1in Eudragit™ L100 and 1:2 in Eudragit™ S100. The polymers form salts anddissolve above pH 5.5 and disperse in water to form latex and thus avoidthe use of organic solvents in the coating process. Eudragit™ L30D-55 isa ready to use aqueous dispersion of Eudragit™ L100-55. The watersolubility of the Eudragit™ S depends on the ratio of free carboxylgroups to the ester groups. The critical factor that influences theperformance of these polymers is the pH value at which dissolutionoccurs. Polymers with ionizable phthalic acid groups dissolve muchfaster and at a lower pH than those with acrylic or methacrylic acidgroups. The presence of plasticizer and the nature of the salt in thedissolution medium also influence the dissolution rate of Eudragit™. Inaddition, the permeability of the film formed may depend on the type ofsolvent used to dissolve Eudragit™ (Dressman, J. B., Amidon, C., Reppas,C. and Shah, V. P., Dissolution testing as a prognostic tool for oraldrug absorption: Immediate release dosage forms, Pharm Res, 15: 11-22,1998.).

Variable combinations of the commercially available acrylic-,methacrylic-, ethylcellulose-based polymers (such as, but not limited tothe Eudragit™ and Surelease® range), as well as other polymers withnatural polysaccharides, including, but not limited to amylose, pectinand guar gum have the potential to customise how, where and when drugsare released from the underlying or embedded solid, semi-solid or liquidforms. There is a need for formulations which will enable thedevelopment of various combinations of controlled release polymers withsolid, semi-solid or liquid drug formulations.

STATEMENTS OF INVENTION

The invention provides an oral composition comprising minicapsuleswherein the minicapsules comprise one or more therapeutic orprophylactic substances in a liquid, semi-solid, or solid core, theminicapsules having release profiles to release the substance in anactive form at one or more sites along the gastrointestinal tract. Theterm active pharmaceutical as used below refers to any suitabletherapeutically and/or prophylactically active substance. The inventionprovides an oral pharmaceutical composition comprising minicapsuleswherein the minicapsules comprise one or more active pharmaceuticalcompound in a liquid, semi-solid or solid core minicapsule format, theminicapsules having release profiles to release the active compound atone or more sites along the gastrointestinal tract where absorption ismaximized or therapeutic efficacy is maximized. Importantly, theinvention ensures that the molecule, regardless of its inherentphysicochemical property, when released from the minicapsule is in asoluble form or is readily soluble in the aqueous GIT environment.

The active pharmaceutical compound(s) may be a small molecule, protein,peptide, nucleic acid, carbohydrate, live organism, component derivedfrom an organism, or any derivative thereof.

The minicapsule may have one layer and may be solid throughout.Alternatively, the minicapsule may have two layers comprising a solidouter shell layer encapsulating a liquid, semi-solid or solid core. Forexample, the minicapsule may have three layers comprising a solid outershell layer; a solid, semi-solid or liquid middle buffer layer; and aliquid, semi-solid or liquid core.

The minicapsules may be modified to enable modified release of theactive(s). For example, a modified release coating may be applied to theouter shell layer of the minicapsule. Alternatively, an outer shelllayer of the minicapsule may be modified to achieve modified release. Inother formats, the minicapsule core or entirety may control the rate ofactive compound release. For example a buffer layer of the minicapsulemay be modified to achieve modified release. Alternatively, the liquid,semi-liquid or solid core of the minicapsule may be modified to achievemodified release. For example, polymeric materials may be used achievemodified release such as polymeric materials that are sensitive to oneor more of pH, time, thickness, erosion, and bacterial breakdown.

The minicapsule may comprise of one layer containing one or more activepharmaceutical agent and that layer controls the release of the activepharmaceutical agent(s).

The active pharmaceutical agent may be in micronised or nanonisedparticles. The active pharmaceutical agent(s) may be in soluble form.Alternatively, the active pharmaceutical agent(s) may be in crystallineform or the active pharmaceutical agent(s) may be in amorphous form.

The active pharmaceutical agent(s) may be released along thegastrointestinal tract in a form that maximises systemic absorption. Forexample, the active pharmaceutical agent(s) may be released along thegastrointestinal tract in a form that maximises lymphatic absorption.Alternatively, the active pharmaceutical agent(s) may be released alongthe gastrointestinal tract in a form that maximises blood brain barrierabsorption. Alternatively, the active pharmaceutical agent(s) may bereleased along the gastrointestinal tract in a form that maximisespre-systemic absorption. Alternatively, the active pharmaceuticalagent(s) may be released along the gastrointestinal tract in a form thatmaximises local gastrointestinal activity. Alternatively, the activepharmaceutical agent(s) may be released along the gastrointestinal tractin a form that maximises gastrointestinal lumen activity. Alternatively,the active pharmaceutical agent(s) may be released along thegastrointestinal tract in a form that maximises chronotherapy. In allcases, the active pharmaceutical agent(s) is released in such that is insoluble when released or is readily soluble in the local GITenvironment.

The active pharmaceutical agent(s) may be retained in the gastric regionfor prolonged periods.

A pharmaceutical active may be in two or more formats, a solidminicapsule form soluble in the small intestine or is pre-solubilisedfor release in the colon and/or ileum.

A composition in accordance with the invention may have more than oneactive pharmaceutical agent which is released at one or more region ofthe gastrointestinal tract. For example, one active may be in a solidminicapsule form soluble in the small intestine while the other activemay be pre-solubilised for release in the colon and/or ileum.

The active pharmaceutical agent(s) may be in a solubility enhancedformat which, when released in the colon, is readily absorbed.

The active pharmaceutical agent(s) may be a small molecule.

The active pharmaceutical agent(s) may be a conjugated small molecule orderivative thereof to enhance permeability, increase lipophilicity,and/or increase hydrophilicity or the like.

The active pharmaceutical agent(s) may be a biopharmaceutical such as apeptide, protein, nucleic acid, carbohydrate, conjugates or derivativesthereof to enhance permeability, increase lipophilicity, increasestability, reduce immunogenicity and/or increase hydrophilicity or thelike.

The composition may contain a protectant such as a proteolytic enzymeinhibitor.

The composition may contain an adhesive entity such as a muco- orbio-adhesive.

The composition may contain an antigen(s) and/or an adjuvant(s) toinduce an intestinal mucosal or a systemic immune response.

The composition may have controlled release as a factor of the shellcoating(s). For example controlled release may be a factor of the shellcomposition. Alternatively, controlled release may be a factor of thecore. The controlled release may be a factor of the shell coating and/orthe shell composition and/or the core constituents.

The minicapsules may be administered in a hard gelatine capsule, asprinkle, a tablet or via a feeding tube such as a nasal gastric tube ora duodenal feeding tube.

The minicapsules may further comprise excipients to maximize solubilityof active pharmaceutical compound(s)

The minicapsules may further comprise excipients to maximizepermeability of the active pharmaceutical compound(s) in the smallintestine.

The composition may further comprise excipients to maximize permeabilityof the active pharmaceutical compound(s) in the ileum, including, butnot limited to sodium caprate, sodium dodecanoate, sodium palmitate,SNAC, chitosan and derivatives thereof, fatty acids, fatty acid esters,polyethers, bile salts, hydroxylase inhibitors, antioxidants and/ornitric oxide donors, including nitric oxide donor groups covalentlyattached to various active pharmaceutical ingredients.

The composition may further comprise excipients to maximize permeabilityof the active pharmaceutical compound(s) in the colon including, but notlimited to sodium caprate, sodium dodecanoate, sodium palmitate, SNAC,chitosan and derivatives thereof, fatty acids, fatty acid esters,polyethers, bile salts, hydroxylase inhibitors, antioxidants and/ornitric oxide donors, including nitric oxide donor groups covalentlyattached to various active pharmaceutical ingredients.

The composition may further comprise excipients to enhance thetherapeutic potential of active pharmaceutical agents in the ileum andcolon including, but not limited to absorption limiters, essential oilssuch as omega 3 oils, natural plant extracts such as neem, ion-exchangeresins, bacteria degradable conjugation linkers such as azo bonds,polysaccharides such as amylose, guar gum, pectin, chitosan, inulin,cyclodextrins, chondroitin sulphate, dextrans, guar gum and locust beangum, nuclear factor kappa B inhibitors, acids such as fumeric acid,citric acid and others, as well as modifications thereof.

The composition may further comprise excipients or other activepharmaceutical or other ingredients to enhance systemic bioavailabilityfollowing absorption in the small intestine including efflux pumpinhibitors, including, but not limited to PgP pump inhibitors, andmetabolism inhibitors, including, but not limited to, cytochrome P450 3Ainhibitors.

The composition may further comprise excipients to reduce systemic sideeffects associated with absorption in the small intestine including, butnot limited to, antioxidants, such as curcuminoids, flavanoids or morespecifically including curcumin, beta-carotene, α-tocopherol, ascorbateor lazaroid.

The pharmaceutical active may be in a solubilised or readily solubleliquid, semi-liquid or solid form.

The pharmaceutical active may be an immunosuppressive, for examplecyclosporine A or tacrolimus or sirolimus or derivatives thereof.

The composition may provide sustained release of the immunosuppressive,in soluble or readily soluble form, throughout the entire length of thegastrointestinal tract.

The composition may facility release over 24 hours, or at different timeperiods throughout 24 hours.

The composition may facilitate absorption over 24 hours.

The composition may be used in the treatment of graft-versus-hostdisease, for example in the treatment of gastro-intestinalgraft-versus-host disease.

The pharmaceutical active immunosuppressive may be released throughoutthe colon and/or ileum.

The composition may be used in the treatment of inflammatory boweldisease.

The pharmaceutical active may be a hydroxylase inhibitor, for example apropyl hydroxylase inhibitor or an asparaginyl hydroxylase inhibitor.

The pharmaceutical active may be DMOG.

The pharmaceutical active may be hydralazine.

The pharmaceutical active may be FG4095.

The composition may be used in the treatment of inflammatory boweldisease.

The pharmaceutical active may be a plant extract.

The pharmaceutical active may be a marine extract.

The pharmaceutical active may be an essential oil.

The composition may be used in the treatment of inflammatory boweldisease.

The composition may be used in the treatment of irritable bowelsyndrome.

The composition may be used in the treatment of constipation.

The composition may be used in the treatment of diarrhoea.

The pharmaceutical active may be a vaccine.

The pharmaceutical active may modulate oral tolerance. For example, theactive entity may be gluten or a gluten derivative.

The composition may be used in the treatment of celiac disease.

The pharmaceutical active may modulate irritable bowel syndrome.

The pharmaceutical active may be a hydoxylase inhibitor.

The pharmaceutical active may be an ion channel blocker.

The pharmaceutical active may be a plant extract.

The pharmaceutical active may be an opioid, for example thepharmaceutical active may be morphine or morphine sulphate.

The opioid may be combined with an opioid-induced constipation modulatorfor example a peripheral opioid receptor antagonist. The peripheralopioid receptor antagonist may be methylnaltrexone. Alternatively, theperipheral opioid receptor antagonist may be naltrexone or naloxone.

The combination opioid and peripheral opioid receptor may be combinedwith an ion-channel blocker for example a calcium channel blocker. Thecalcium channel blocker may be nimodipine.

The composition may have an extended opioid effect and constipation maybe limited.

The combination opioid and peripheral opioid receptor may be combinedwith an ion-channel blocker for example a calcium channel blocker. Thecalcium channel blocker may be nimodipine.

The composition may have an extended opioid effect, constipation may belimited and the product may be tamper-proofed.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more clearly understood from the followingdescription of an embodiment thereof, given by way of example only, withreference to the accompanying drawings, in which:—

FIG. 1 is a schematic of a liquid-filled minicapsule, wherein the activeis solubilised, with controlled release polymer coatings. The open arrowrepresents the release of a drug molecule into the external medium,where it is fully soluble when released (Format 1);

FIG. 2 is a schematic of a Semi-solid- or solid-filledminicapsule/minisphere, wherein the active is solubilised or in asuspension form, with controlled release polymer coatings; The openarrow represents the release of a drug molecule into the externalmedium, where it is fully soluble when released (Format 2);

FIG. 3 is a schematic of a gelling agent encapsulating enhancedsolubilised or permeabilised active substances, including substances inmicronised or nanonised form, primarily in a dispersion form, eithercrystalline or amorphous formats; The open arrow represents the releaseof a drug molecule into the external medium, where it is fully solublewhen released (Format 3);

FIG. 4 is a schematic of active substances, in crystalline or amorphousform, blended with extrudable or other polymers which are melt-extruded,granulated, drug layered, spheronised or otherwise processed which maybe further coated to permit controlled or targeted release along thegastrointestinal tract or, alternatively, are inherently controlledrelease; The open arrow represents the release of a drug molecule intothe external medium, where it is fully soluble when released (Format 4);

FIG. 5 is a graph showing the dissolution profile for uncoatedtacrolimus minicapsules (Format 1);

FIG. 6 is a graph showing the dissolution profile for tacrolimusminicapsules coated with 12.5% Eudragit RS30D followed by 25% Eudragit™FS30D (Format 1);

FIG. 7 is a graph showing the dissolution profile for 15% weight gainEudragit™ RS30D/25% weight gain Surlease®—coated tacrolimus minicapsules(Format 1);

FIG. 8 represents the serum IgG responses following immunisation withOVA and OVA and poly I:C after the initial series of immunisations andparticular after booster immunisation. The dots refer to antibody titresin individual mice and the line represents the mean titre for the group(Format 2);

FIG. 9 represents intestinal mucosal IgA and IgG responses followingimmunisation with of mice with OVA in solution or uncoated and coatedminicapsules containing OVA and poly I:C. The dots refer to antibodytitres in individual mice and the line represents the mean titre for thegroup (Format 2);

FIG. 10 represents splenic T-cell responses in mice followingimmunisation of mice with uncoated and coated minicapsules containingOVA with poly IC, as measured by IL-17 cytokine secretion and IFN-γresponse on re-stimulation with antigen (Format 2);

FIG. 11 represents splenic T-cell responses in mice followingimmunisation of mice with uncoated and coated minicapsules containingOVA with poly IC, as measured by IL-4, IL-5 and IL-10 cytokine secretionand IFN-γ response on re-stimulation with antigen (Format 2);

FIG. 12 represents mesenteric lymph node T-cell responses in micefollowing immunisation with uncoated and coated minicapsules containingOVA with poly IC, as measured by secretion of IL-4, IL-5 and IFN-γresponse on re-stimulation with antigen (Format 2);

FIG. 13 is a graph showing the dissolution profile for uncoatedmicronized tacrolimus solid minicapsules (Format 3);

FIG. 14 is a graph showing the dissolution profile for 10% weight gainSurelease® coated micronized tacrolimus solid minicapsules (Format 3);

FIG. 15 is a graph showing the dissolution profile for 15% weight gainSurelease® coated micronized tacrolimus solid minicapsules (Format 3);

FIG. 16 is a graph showing the dissolution profile for 20% weight gainSurelease® coated micronized tacrolimus solid minicapsules (Format 3);

FIG. 17 is a graph showing the dissolution profile for 25% weight gainSurelease® coated micronized tacrolimus solid minicapsules (Format 3);

FIG. 18 is a graph showing the dissolution profile for 30% weight gainSurelease® coated micronized tacrolimus solid minicapsules (Format 3);

FIG. 19 is a graph showing the dissolution profile of micronizedtacrolimus from minicapsules coated with a range (0-30%) of Surelease®weight gains (Format 3);

FIG. 20 is a graph representing the packed cell volume (% PCV) ofDSS-induced colitis mice treated with DMOG IP (8 mg every second day)and orally in immediate release beads (DSS-beads coated with 12.5%Surelease®—DMOG: 0.25 mg/day) or colon-specific coated beads (DSS-COATbeads coated with 22% Surelease®—DMOG: 0.25 mg/day) for 7 days, with 6mice in each group (Format 4);

FIG. 21 is a graph showing the Disease Activity Index (DAI) ofDSS-induced colitis mice treated with DMOG IP (8 mg DMOG every secondday) and orally in immediate release beads (DSS-beads coated with 12.5%Surelease®—DMOG: 0.25 mg/day) or colon-specific coated beads (DSS-COATbeads coated with 22% Surelease®—DMOG: 0.25 mg/day) for 7 days, with 6mice in each group (Format 4);

FIG. 22 is a graph showing the average colon length of DSS-inducedcolitis mice treated with DMOG IP (8 mg DMOG every second day) andorally in immediate release beads (DSS-beads coated with 12.5%Surelease®—DMOG: 0.25 mg/day) or colon-specific coated beads (DSS-COATbeads coated with 22% Surelease®—DMOG: 0.25 mg/day) for 7 days, with 6mice in each group (Format 4);

DETAILED DESCRIPTION

The controlled release of active pharmaceutical agents is only trulyuseful if the agent is available to interact with its receptor or siteof action in an active form. Unless the agent is in a fully soluble formit is unlikely to interact with its intended receptor or exert itsdesired action. The invention is a drug delivery format that enables therelease of an active(s) from the format in soluble or readily-solubleform.

As the invention permits the release of the active in soluble orreadily-soluble form, it thus enables a true once-daily drugformulation, especially for a small molecule drug with poorwater-solubility, possibly with limited stability or a short half-life,as the drug is absorbed not only in the small intestine but also in thecolon.

The invention provides an oral drug delivery technology that permits thecolon-specific release of pre- or readily-solubilised drugs in tandemwith a controlled release formulation that permits release andabsorption in the small intestine, ileum and/or colon of soluble orreadily-soluble drug molecules to ensure true once-daily formulationsfor hydrophilic, hydrophobic or lipophilic small molecule drugs withvariable stability.

As the invention is comprised of a multitude of separate minicapsules,either containing liquid, semi-solid or solid formulations, theinvention enables the development of novel combination therapies in asingle dosage form, each component of the combination having distinctrelease profiles, the release being inherent to the core formulation,the shell or the entirety of the minicapsule or some additional polymercoating thereon.

In addition to enabling once-daily delivery of the above classes ofsmall molecules, colon delivery is advantageous as an effective drugdelivery mechanism for certain drugs, including biopharmaceuticals andvaccines, drugs formulated for enhanced lymphatic absorptions as well asfor enhanced treatment of diseases of colon (ulcerative colitis, Chron'sdisease, Gastro-Intestinal Graft Versus Host Disease (GI-GVHD),Irritable Bowel Syndrome, constipation, diarrhoea, carcinomas and otherinfections) whereby high local concentration can be achieved whileminimizing side effects that occur because of release of drugs in theupper GIT or unnecessary systemic absorption. The colon is rich inlymphoid tissue, uptake of antigens into the mast cells of the colonicmucosa produces rapid local production of antibodies and this helps inefficient vaccine delivery (Sarasija, S. and Hota, A., Colon-specificdrug delivery systems. Ind J Pharm Sci, 62: 1-8, 2000).

The colon is a site where a drug molecule, particularly but notexclusively hydrophilic, that has limited intestinal absorption may havean improved bioavailability. The colon is recognized as having asomewhat less hostile environment with less diversity and intensity ofactivity than the stomach and small intestine. Additionally, the colonhas a longer retention time and appears highly responsive to agents thatenhance the absorption of poorly absorbed drugs. Apart from retarding ortargeting dosage forms, a reliable colonic drug delivery is also animportant for the colonic absorption of perorally applied, undigested,unchanged and fully active peptide drugs. As the large intestine isrelatively free of peptidases such special delivery systems will have agreater chance to get their drug sufficiently absorbed after peroralapplication.

Traditional dosage forms in which an immediate release (IR) dosage formis administered at periodic intervals typically gives rise to apulsatile plasma profile, related to the time of ingestion and usuallywithin a short period following such ingestion. Where release from thedosage form is rapid or ‘immediate’, the peak in the plasma drugconcentration is observed after administration of each IR dose withtroughs or low plasma concentrations obvious between consecutiveadministration time points. The pulsatile plasma profiles resulting fromsuch dosage regimes may affect the pharmacological and therapeuticeffect, thereby resulting in beneficial or detrimental consequences forcertain drug therapies. In some instances, the fall off of the plasmaconcentration of the active ingredient between peaks results in awash-out period and may contribute to a reduction in or prevention ofpatient tolerance to various types of drugs. Pulsatile release formatshave proven successful for a range of drugs but many others have notbenefited from such delivery systems and it has not been particularlysuccessful for colon-specific or the development of true once-dailyforms of certain drug classes, including low solubility small moleculesand biopharmaceuticals.

Alternatively, other drugs may not be absorbed in the small intestinebut may exhibit greater absorption levels in the colon. The inventionprovides drug delivery technologies to enhance absorption ofhydrophilic, hydrophobic or lipophilic drugs from the colon. By-passingthe gastric and small intestinal regions, and releasing drugs intact andin soluble as well as permeabilised form directly into the colonenhances absorption of the drug from the colon.

Examples of drugs that have demonstrated limited colonic absorptioninclude Tacrolimus, Cyclosporine, Carvedilol, Budesonide and Celecoxib.

Tacrolimus, a macrolide agent is an immunosuppressant and is primarilyused in post-organ transplant patients to prevent organ rejection.Tacrolimus is differentially absorbed from in different regions of thegastrointestinal tract, being optimally absorbed from the smallintestine, with ileum and colonic absorption efficiency dropping to halfthat observed for the small intestine.

Also, a food effect is observed. After absorption from thegastrointestinal tract, drug effects persist for 8-12 hours after oraladministration of conventional IR tablets. The total dosage is typicallyin the range of 2.5-10 mg per day, in exceptional cases rising to 20mg/day. Under conventional dosage regimes, Tacrolimus is given twicedaily, typically with one dose given before breakfast and a second dosegiven in the late afternoon. Adverse effects, due to the initial rapidabsorption from the small intestine results in above therapeutic plasmaconcentrations, associated with tacrolimus treatment includenephrotoxicity and the development of patient infection due toimmunosuppression. There is a need for a controlled release format thatprevents toxic side effects while enhancing absorption from the ileumand colon.

Cyclosporine is a cyclic polypeptide immunosuppressant agent. Formulatedas an emulsion, it is indicated for the prevention of organ rejection inkidney, liver and heart transplants, for the treatment of severe activerheumatoid arthritis (RA) and severe recalcitrant plaque psoriasis.Other potential indications include Bechet's disease, anaemia, nephroticsyndrome and Graft Versus Host Disease (GVHD), includingGastro-Intestinal Graft Versus Host Disease (GI-GVHD). Significantnephrotoxicity and hepatotoxicity is a serious, dose-related side effectassociated with long term use of cyclosporine. This is most likely dueto the bolus-like release from the only available administration format,the large soft-gel capsule. In a study by Sandborn et al. the relativesystemic absorption of cyclosporine following oral and intravenous aswell as oil- and a water-based enemas was determined. Based onnegligible plasma cyclosporine concentrations following enemaadministration, it was suggested that cyclosporine, even whensolubilised, is poorly absorbed from the colon. Despite the lack ofcolonic absorption the enemas demonstrated considerable efficacy in thetreatment of inflammatory bowel disease. Interestingly, orallyadministered cyclosporine demonstrated very limited efficacy in thetreatment of inflammatory bowel disease. This is most likely due to thefact that the cyclosporine was systemically absorbed from the smallintestine or degraded in the intestine with little or no intactcyclosporine reaching the colon to treat what is considered by some tobe a cell mediated immune dysfunction at the level of the intestinalmucosa. Thus, based on the associated side effects, there exists a needfor a controlled release formulation to prevent dose-related sideeffects and also a need for an orally delivered, colon-specific releasedproduct for the treatment of colon associated inflammatory bowel diseasewithout any associated dose related side-effects.

Additionally, for conditions that may affect the entiregastro-intestinal tract, including the small intestine, such as Crohn'sDisease and GI-GVHD, a sustained release format of pre-solubilisedCyclosporine, exhibiting limited systemic absorption is desirable.

Furthermore, in addition to cyclosporine and tacrolimus, otherimmunosuppressant, including, but not limited to sirolimus may be wouldbenefit from an improved controlled or targeted release drug deliverytechnology. All immunosuppressant agents, including but not limited totacrolimus, cyclosporine and sirolimus, have the potential to benefitfrom the development of a pre-solubilised, colon-specific drug deliveryformat in the context of inflammatory bowel diseases, including Crohn'sDisease, Ulcerative Colitis and GI-Graft-Versus-Host Disease.

Carvedilol is an antioxidant and non-selective alpha- and beta-blockerused in the management of essential hypertension, alone or incombination with other antihypertensive agents, and for the treatment ofmild-to-severe heart failure of ischemic or cardiomyopathic origin.Other approved indications, include the reduction of cardiovascularmortality in clinically stable patients who have survived the acutephase of a myocardial infarction and a left ventricular ejectionfraction of less than or equal to 40%. Carvedilol is poorly watersoluble with highest solubility at pH 5.0, is absorbed rapidly from thesmall intestine, reaching maximum plasma concentration within two hoursand has a half-life of 7-10 hours. It undergoes extensive first-passmetabolism resulting in an absolute bioavailability of approximately25%. While a food effect is suggested, the pharmacokinetics for themarketed product, Coreg™, is linearly related to dose. It has beendemonstrated that absorption decreases within the intestine withrelative absorption in the jejunum, ileum and colon of approximately56%, 28% and 7% respectively. As a BSC Class II product, its absorptionis considered solubility limited, rather than permeability limited.Thus, a controlled release format to target initial release into thejejunum followed by release of the active in soluble form into the colonis desirable for the development of a true once-daily carvedilolformulation.

Budesonide is a poorly-soluble, synthetic steroid of the glucocorticoidfamily. The naturally-occurring hormone whose actions budesonide mimics,is cortisol or hydrocortisone which is produced by the adrenal glands.Glucocorticoid steroids have potent anti-inflammatory actions.

Reformulated as Entocort EC, budesonide is released from granules in theileum of the small intestine and the right (proximal) colon, where theinflammation of Crohn's disease occurs. Budesonide acts directly bycontact with the ileum and colon. The budesonide that is absorbed intothe body travels to the liver where it is broken-down and eliminatedfrom the body. This prevents the majority of the absorbed drug frombeing distributed to the rest of the body. As a result, budesonidecauses fewer severe side effects throughout the body than othercorticosteroids. The effectiveness of budesonide in the treatment ofCrohn's and broader Inflammatory Bowel Diseases could be enhanced ifdeveloped as a pre-solubilised, ileum- or colon-specific drug deliveryformat.

Celecoxib is an oral COX-2 inhibitor, developed and indicated fortreating the signs and symptoms of adult rheumatoid arthritis (RA),osteoarthritis (OA) and ankylosing spondylitis (AS); for managing acutepain in adults; for treating primary dysmenorrhea; and for reducing thenumber of colorectal polyps in familial adenomatous polyposis (FAP) andas an adjunct to related care, including surgery, with potentialapplications in post-traumatic pain and tooth extraction pain. In April2005, following the withdrawal of Vioxx, an FDA panel concluded thatCelebrex carried a ‘moderate’ cardiovascular risk. A poorly solubledrug, celecoxib is administered in capsule format. To focus on the FAPindication, colon specific delivery would be advantageous as a targeteddelivery system and to reduce any potential side effect risks.

As the above cited drug examples have proven difficult to formulate,true once-daily formats have proven difficult to develop. To overcomethis issue, enhanced delivery systems with the potential to combineaspects of any of solubility, permeability and stability enhancementalong with gastro-intestinal targeted release are required.

The invention is particularly applicable to chronotherapeutics. Based onthe body's natural circadian rhythms, certain disease conditions lessenor worsen depending on the time of day or night. Scientific and medicalresearch has proven that many physiological biochemical pathways followthe natural circadian body rhythms. As a consequence, cardiovascularconditions such as angina pectoris and myocardial infarction are morecommon in the early hours of the morning while the sympathetic nervoussystem relaxes during the night hours, thereby lessening the need fortherapeutics that affect this system, such as beta blockers (Lemmer,Chronopharmacology, Marcel Decker, 1989; Lemmer, Pharmacol. Ther.,111:629, 2006). Likewise, allergies and asthma attacks are more commonduring the night-time hours (Reinberg et al, Eur J Clin Pharmacol14:245, 1978). Furthermore, absorption from and perfusion of the smallintestine varies according to the time of day or night while themotility of the gastrointestinal tract and gastric emptying vary fromday to night (Lemmer et al., Chronobiol Int 8:485, 1991; Lemmer andNold, Br J Clin Pharmacol 32:627, 1991, Goo et al., Gastroenterology93:515, 1987)

The invention enables successful colonic delivery. In the invention adrug is protected from absorption and/or the environment of the uppergastrointestinal tract (GIT) but allows abrupt and/or sustained releaseinto the proximal colon, which is the optimum site for colon-targeteddelivery of drugs. Such colon targeting is particularly of value for thetreatment of diseases of colon such as Crohn's diseases, ulcerativecolitis, colorectal cancer and amebiasis. Small molecules, peptides,proteins, antibodies, including antibody fragments, oligonucleotides,including siRNAs and vaccines pose potential candidature for colontargeted drug delivery.

In various embodiments comprising a membrane-controlled dosage form, thepolymeric material comprises methacrylic acid co-polymers, ammoniomethacrylate co-polymers, or mixtures thereof. Methacrylic acidco-polymers such as EUDRAGIT™ S and EUDRAGIT™ L (Evonik) are suitablefor use in the controlled release formulations of the present invention.These polymers are gastroresistant and enterosoluble polymers. Theirpolymer films are insoluble in pure water and diluted acids. Theydissolve at higher pHs, depending on their content of carboxylic acid.EUDRAGIT™ S and EUDRAGIT™ L can be used as single components in thepolymer coating or in combination in any ratio. By using a combinationof the polymers, the polymeric material can exhibit a solubility at a pHbetween the pHs at which EUDRAGIT™ L and EUDRAGIT™ S are separatelysoluble.

The membrane coating can comprise a polymeric material comprising amajor proportion (i.e., greater than 50% of the total polymeric content)of at least one pharmaceutically acceptable water-soluble polymers, andoptionally a minor proportion (i.e., less than 50% of the totalpolymeric content) of at least one pharmaceutically acceptable waterinsoluble polymers. Alternatively, the membrane coating can comprise apolymeric material comprising a major proportion (i.e., greater than 50%of the total polymeric content) of at least one pharmaceuticallyacceptable water insoluble polymers, and optionally a minor proportion(i.e., less than 50% of the total polymeric content) of at least onepharmaceutically acceptable water-soluble polymer.

Ammonio methacrylate co-polymers such as EUDRAGIT™ RS and EUDRAGIT™ RL(Evonik) are suitable for use in the modified release formulations ofthe present invention. These polymers are insoluble in pure water,dilute acids, buffer solutions, or digestive fluids over the entirephysiological pH range. The polymers swell in water and digestive fluidsindependently of pH. In the swollen state, they are then permeable towater and dissolved active agents. The permeability of the polymersdepends on the ratio of ethylacrylate (EA), methyl methacrylate (MMA),and trimethylammonioethyl methacrylate chloride (TAMCl) groups in thepolymer. Those polymers having EA:MMA:TAMCl ratios of 1:2:0.2 (EUDRAGIT™RL) are more permeable than those with ratios of 1:2:0.1 (EUDRAGIT™ RS).Polymers of EUDRAGIT™ RL are insoluble polymers of high permeability.Polymers of EUDRAGIT™ RS are insoluble films of low permeability.

The amino methacrylate co-polymers can be combined in any desired ratio,and the ratio can be modified to modify the rate of drug release. Forexample, a ratio of EUDRAGIT™ RS:EUDRAGIT™ RL of 90:10 can be used.Alternatively, the ratio of EUDRAGIT™ RS:EUDRAGIT™ RL can be about 100:0to about 80:20, or about 100:0 to about 90:10, or any ratio in between.In such formulations, the less permeable polymer EUDRAGIT™ RS wouldgenerally comprise the majority of the polymeric material with the moresoluble RL, when it dissolves, permitting creating gaps through whichsolutes can enter the core and dissolved pharmaceutical actives escapein a controlled manner.

The amino methacrylate co-polymers can be combined with the methacrylicacid co-polymers within the polymeric material in order to achieve thedesired delay in the release of the drug. Ratios of ammonio methacrylateco-polymer (e.g., EUDRAGIT™ RS) to methacrylic acid co-polymer in therange of about 99:1 to about 20:80 can be used. The two types ofpolymers can also be combined into the same polymeric material, orprovided as separate coats that are applied to the core.

Eudragit™ FS 30 D is an anionic aqueous-based acrylic polymericdispersion consisting of methacrylic acid, methyl acrylate, and methylmethacrylate and is pH sensitive. This polymer contains fewer carboxylgroups and thus dissolves at a higher pH (>6.5). The advantage of such asystem is that it can be easily manufactured on a large scale in areasonable processing time using conventional powder layering andfluidized bed coating techniques. In a study by Gupta et al (Int JPharm, 213: 83-91, 2001) Eudragit FS 30 D demonstrated its potential forcolonic delivery by resisting drug release up to pH 6.5 and thecombination of Eudragit™ RL and RS proved successful for the sustaineddelivery of 5-ASA at the pH of the colon. Thus, Eudragit™ FS 30 D aloneor with other controlled release polymers holds great potential toenable delivery of minicapsule formulations specifically to the colon.

In addition to the EUDRAGIT™ polymers described above, a number of othersuch copolymers can be used to control drug release. These includemethacrylate ester co-polymers such as the EUDRAGIT™ NE and EUDRAGIT™ NMranges. Further information on the EUDRAGIT™ polymers can be found in“Chemistry and Application Properties of Polymethacrylate CoatingSystems,” in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,ed. James McGinity, Marcel Dekker Inc., New York, pg 109-114.

Several derivatives of hydroxypropyl methylcellulose (HPMC) also exhibitpH dependent solubility. Shin-Etsu Chemical Co., Ltd. esterified HPMCwith phthalic anhydride to produce hydroxypropyl methylcellulosephthalate (HPMCP), which rapidly dissolves in the upper intestinaltract. Due to the limited compatibility of HPMCP with several types ofplasticizers, hydroxypropyl methylcellulose acetate succinate (HPMCAS)was developed. The presence of ionizable carboxyl groups in the HPMCASstructure cause the polymer to solubilize at high pH (>5.5 for the LFgrade and >6.8 for the HF grade). This polymer exhibits goodcompatibility with a variety of plasticizing agents and is commerciallyavailable from Shin-Etsu Chemical Co. Ltd. under the proprietary nameAQOAT® in a powdered form to be redispersed in water.

Surelease® dispersion is a unique combination of film-forming polymer,plasticizer and stabilizers. Designed for sustained release and tastemasking applications, Surelease is an easy-to-use, totally aqueouscoating system using ethylcellulose as the release rate controllingpolymer. The dispersion provides the flexibility to adjust drug releaserates with reproducible profiles that are relatively insensitive to pH.The principal means of drug release is by diffusion through theSurelease dispersion membrane and is directly controlled by filmthickness. Increasing or decreasing the quantity of Surelease® appliedcan easily modify the rate of release. With Surelease dispersion,reproducible drug release profiles are consistent right through fromdevelopment to scale-up and production processes.

In addition to the EUDRAGIT™ and Surelease® polymers discussed above,other enteric, or pH-dependent, polymers can be used. Such polymers caninclude phthalate, butyrate, succinate, and/or mellitate groups. Suchpolymers include, but are not limited to, cellulose acetate phthalate,cellulose acetate succinate, cellulose hydrogen phthalate, celluloseacetate trimellitate, hydroxypropyl-methylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate, starch acetatephthalate, amylose acetate phthalate, polyvinyl acetate phthalate, andpolyvinyl butyrate phthalate. Additionally, where compatible, anycombination of polymer may be blended to provide additional controlled-or targeted-release profiles.

The coating membrane can further comprise at least one soluble excipientto increase the permeability of the polymeric material. Suitably, the atleast one soluble excipient is selected from among a soluble polymer, asurfactant, an alkali metal salt, an organic acid, a sugar, and a sugaralcohol. Such soluble excipients include, but are not limited to,polyvinyl pyrrolidone, polyethylene glycol, sodium chloride, surfactantssuch as sodium lauryl sulfate and polysorbates, organic acids such asacetic acid, adipic acid, citric acid, fumaric acid, glutaric acid,malic acid, succinic acid, and tartaric acid, sugars such as dextrose,fructose, glucose, lactose, and sucrose, sugar alcohols such aslactitol, maltitol, mannitol, sorbitol, and xylitol, xanthan gum,dextrins, and maltodextrins. In some embodiments, polyvinyl pyrrolidone,mannitol, and/or polyethylene glycol can be used as soluble excipients.The at least one soluble excipient can be used in an amount ranging fromabout 1% to about 10% by weight, based on the total dry weight of thepolymer. The coating process can be carried out by any suitable means,for example, by using a perforated pan system such as the GLATT,ACCELACOTA, Vector, Diosna, O'Hara, HICOATER or other such coatingprocess equipment. Seamless minicapsules may be manufactured using themethod described in U.S. Pat. No. 5,882,680 (Freund), the entirecontents of which are incorporated herein by reference.

The modifications in the rates of release, such as to create a delay orextension in release, can be achieved in any number of ways. Mechanismscan be dependent or independent of local pH in the intestine, and canalso rely on local enzymatic activity to achieve the desired effect.Examples of modified-release formulations are known in the art and aredescribed, for example, in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566.

A number of modified dosage forms suitable for use are described below.A more detailed discussion of such forms can also be found in, forexample The Handbook of Pharmaceutical Controlled Release Technology, D.L. Wise (ed.), Marcel Decker, Inc., New York (2000); and also inTreatise on Controlled Drug Delivery: Fundamentals, Optimization, andApplications, A. Kydonieus (ed.), Marcel Decker, Inc., New York, (1992),the relevant contents of each of which are hereby incorporated byreference for this purpose. Examples of modified-release formulationsinclude but are not limited to, membrane-modified, matrix, osmotic, andion-exchange systems. All of these can be in the form of single-unit ormulti-unit dosage forms, as alluded to above.

With membrane-modified extended-release dosage forms, a semi-permeablemembrane can surround the formulation containing the active substance ofinterest. Semi-permeable membranes include those that are permeable to agreater or lesser extent to both water and solute. This membrane caninclude water-insoluble and/or water-soluble polymers, and can exhibitpH-dependent and/or pH-independent solubility characteristics. Polymersof these types are described in detail below. Generally, thecharacteristics of the polymeric membrane, which may be determined by,e.g., the composition of the membrane, will determine the nature ofrelease from the dosage form.

In particular, the present invention provides for formulations ofminicapsules or minispheres wherein the modified release is dependentupon, where appropriate, any one of the core formulation constituents,the shell composition or the shell coating. The minicapsules orminispheres may be produced through the utilisation of surface tensionof one or more different solutions which when ejected through an orificeor nozzle with a certain diameter and subject to specific frequenciesand gravitational flow, forms into a spherical form and falls into acooling air flow or into a cooling or hardening solution and the outershell solution where it is gelled or solidified. This briefly describesthe formation of seamless minispheres. According to prior art the coresolution is mainly a hydrophobic solution or suspension. The outer shellsolution can be any gel forming agent but is normally gelatine- oralginate-based based but may also include polymers or other materialsthat enable controlled release. However a hydrophilic solution can alsobe encapsulated with the existence of an intermediate solution, whichcan avoid the direct contact of the hydrophilic core solution with theouter shell. With the nozzle having a single orifice, a minicapsule or abead of shell/core mixed suspension can be processed and may further beprocessed using a melt extruder. With the nozzle having two orifices(centre and outer), a hydrophobic solution can be encapsulated. Whereappropriate, it may be possible that both the core and/or shell may becomprised of a material or material composites that have been processedby a wet- or dry-extrusion mechanism, melt or otherwise fluidized priorto mixing or extrusion. Ideally, to enable drug content and releaseconsistency, it is preferred that all processes will result in fairlyuniform morphologies with a relatively smooth surface to facilitatequite even coating layers to be added in a uniform manner. With thenozzle having one or more orifices seamless minicapsules for variousapplications can be processed using minicapsule processing equipmentenabled by, but not limited to, Freund Spherex, ITAS/Lambo Globex orInotech processing equipment. As outlined above the coating process canbe carried out by any suitable means, for example, by using a perforatedpan or fluidized-baed system such as the GLATT, Vector, ACCELACOTA,Diosna, O'Hara and/or HICOATER processing equipment.

The result is modified release compositions that in operation deliverone or more active ingredients in a unique, bimodal or multimodalmanner. The present invention further relates to solid oral dosageforms, sachets or suppositories containing such multiple minicapsule orminisphere controlled release compositions as well as methods fordelivering one or more active ingredients to a patient in a bimodal ormultimodal manner. Furthermore, the invention permits targeted releaseof orally delivered formulations to specific regions of thegastrointestinal tract to maximize absorption, confer protection on thepayload, to optimize treatment of diseased intestinal tissue or enhanceoral bioavailability. Additionally, the invention enables one or morepharmaceutical active to be administered sequentially or concomitantlyto improve disease treatment and management and to benefit from thebody's natural circadian rhythms. The invention also permits the releaseof pharmaceutical actives into the ileum and colon for the enhancedtreatment of local intestinal diseases or to facilitate the absorptionof active pharmaceutical agents, including biopharmaceuticals such aspeptide and proteins.

The invention enables a pharmaceutical agent, small molecule ormacromolecule, to be clinically effective, to reach its intended targetin an active form, either as the native compound or an active metaboliteof the compound. The use of enteric polymer coatings protects thecontents of minicapsules from gastric acid degradation while othercolon-specific coatings permit release of minicapsule contents only inthe colon where the proteolytic enzyme content is significantly lessthan in the small intestine. Thus, by controlling the minicapsulecoatings the invention provides formulations that ensure that the activecontents are released intact at sites where absorption or therapeuticactivity is optimal.

In the invention, for drugs where systemic bioavailability is critical,that transport of the active agent from the intestinal or colonic lumento the blood or lymphatic system is maximized. As the physicochemicalproperties of drugs vary widely absorption of different drug classes,from hydrophilic, hydrophobic to lipophilic, are absorbed to varyingextents as they pass along the gastrointestinal tract from stomach tocolon. In general, the more lipophilic agents are more readily absorbedfrom the entire intestine than are hydrophilic agents. Where lipophilicagents exhibit poor permeability they are often formulated as micro- orother emulsions that permit interaction with bile salts which enhancesabsorption in the small intestine. To enhance hydrophilic intestinalpermeability various approaches have been adopted, including thedevelopment of lipid-based conjugates which confer upon the active agenta more lipid-like nature which permits enhanced small intestinalpermeability and hence systemic bioavailability. The potentialapplications include, but are not limited to, anticancer agents totarget metastatic cancerous cells in the lymphatic system, vaccines,immunomodulators, including immunostimulators, agents that undergoextensive first-pass effects in the liver, as well as to enhance therelative half-live of active pharmaceuticals in patients with shortbowels and where absorption is limited to the intact small intestine.Where the absorption of small molecules with limited half-lives that aresystemically absorbed only through the small intestine is required, thedevelopment of controlled release floating systems, whereby the system,in this instance controlled-release multiple minicapsules, is buoyant inthe gastric environment may be enabled by this invention.

The invention relates to drug delivery in the colon which has beenlargely overlooked from a drug delivery perspective. Mainly havingevolved to regulate electrolyte balance and to further breakdown complexcarbohydrate structures there is a significant flow of water from thecolonic lumen into the body. In addition, the colon is home to a naturalbacterial flora to degrade complex carbohydrates to ensure effectiveexcretion, provide much needed fibre and some nutrient absorption. Witha much lower concentration of proteolytic and other enzymes populated inthe colon, it is a much more benign environment for proteins andpeptides as well as other biological entities such as carbohydrates andnucleic acids. From a drug delivery perspective, the colon presents anumber of interesting possibilities: the bacteria can be harnessed tobreak down controlled release coatings that are resistant to acidicbreakdown as well as pH differentials; the benign environment ensurethan active pharmaceuticals, including biopharmaceuticals, are lesslikely to be degraded if released locally into the colon; the almostcontinuous flow of fluids from the colonic lumen to the bloodstream maybe harnessed to carry hydrophilic entities from the intestine to thelumen. Finally, the long transit time in the colon, ranging form 10-20hours provides greater residence and potential for interaction with thecolonic mucus and epithelial cells leading to enhanced absorption.

Technologically, this invention is based on various modifications ofbasic one- or multi-layered minicapsules, modulating the core, the shellor the coating to permit enhanced solubility and permeability of thedrug or other active or non-active entity as well as conferringprotection on drugs or entities that are susceptible to various forms ofintestinal, mucosal or systemic degradation and targeted release of thetherapeutically-active or -inactive entities to predetermined regions ofthe gastrointestinal tract.

In addition to the above minicapsule modifications, the presentinvention provides the coating of minicapsules or minispheres with amuco- or bio-adhesive entity which will ensure that they first adhere tothe mucosa prior to releasing the fragile payload. The advantages thusenabled include further protection of the active entities but alsorelease of the actives proximal to the site of absorption. As absorptionis, in part, related to the surface area exposed to the active as wellas the concentration gradient from intestinal luminal side to theintestinal basal side, the higher local yet dispersed concentration hasgreater potential to ensure enhanced absorption, not only of hydrophilicdrugs, but also lipophilic or hydrophobic drugs.

A barrier to effective colonic delivery of hydrophobic and lipophilicdrugs is that the colon did not evolve to solubilize foodstuffs andother entities but rather to ensure electrolyte balance and maximizefibre breakdown and fermentation. The colon remains very porous tohydrophilic entities. By delivering hydrophobic or lipophilic drugs tothe colon in a pre-solubilised or readily soluble format and releasingsuch in the colon, the potential for absorption is enhancedsignificantly. The present invention permits the encapsulation ofpre-solubilized or readily soluble drugs in liquid or hydrolysablesemi-solids or solids into the minicapsule core and then modulation ofthe shell to include intestinal- or colon-controlled release polymers orcoating the shell with same. The result is release of optimizedformulations at specific sites along the intestinal tract for maximaltherapeutic efficacy or systemic absorption.

Likewise, delivery of formulations that are readily broken down in anaqueous environment or a bacteria rich environment has the potential,when coated with colon-specific controlled release polymers or includeentities that are degraded by bacteria have the potential to protectsusceptible entities from the gastric or intestinal environment yetensure that they are released intact in the colon where, once liberated,will be readily absorbed. Redox-sensitive, pectin-, alginate-, chitosan-or other bacterially susceptible polymer-based matrices, coatings orother sustained release formulations, liquid, semi-solid or solid, canbe encapsulated into or coated onto one- or multi-layered minicapsules.

The formulations of the present invention can exist as multi-unit orsingle-unit formulations. The term “multi-unit” as used herein means aplurality of discrete or aggregated minicapsules, minispheres,particles, beads, pellets, granules, tablets, or mixtures thereof, forexample, without regard to their size, shape, or morphology. Single-unitformulations include, for example, tablets, hard gelatin capsules,caplets, and pills.

The methods and formulations of the present invention are intended toencompass all possible combinations of components that exhibitmodified-release and immediate-release properties. For example, aformulation and/or method of the invention can contain components thatexhibit extended-release and immediate-release properties, or bothdelayed-release and immediate-release properties, or bothextended-release and delayed-release properties, or a combination of allthree properties. For example, a multi-minicapsule or multi-minisphereformulation including both immediate-release and extended-releasecomponents can be combined in a capsule, which is then coated with anenteric coat to provide a delayed-release effect. Or, for example, adelayed- and extended-release caplet may comprise a plurality ofdiscrete extended-release particles held together with a binder in thecaplet, which is coated with an enteric coating to create a delay indissolution.

As used herein, the term “modified-release” formulation or dosage formincludes pharmaceutical preparations that achieve a desired release ofthe drug from the formulation. A modified-release formulation can bedesigned to modify the manner in which the active ingredient is exposedto the desired target. For example, a modified-release formulation canbe designed to focus the delivery of the active agent entirely in thedistal large intestine, beginning at the cecum, and continuing throughthe ascending, transverse, and descending colon, and ending in thesigmoid colon. Alternatively, for example, a modified-releasecomposition can be designed to focus the delivery of the drug in theproximal small intestine, beginning at the duodenum and ending at theileum. In still other examples, the modified-release formulations can bedesigned to begin releasing active agent in the jejunum and end theirrelease in the transverse colon. The possibilities and combinations arenumerous, and are clearly not limited to these examples.

The term “modified-release” encompasses “extended-release” and“delayed-release” formulations, as well as formulations having bothextended-release and delayed-release characteristics. An“extended-release” formulation can extend the period over which drug isreleased or targeted to the desired site. A “delayed-release”formulation can be designed to delay the release of the pharmaceuticallyactive compound for a specified period. Such formulations are referredto herein as “delayed-release” or “delayed-onset” formulations or dosageforms. Modified-release formulations of the present invention includethose that exhibit both a delayed- and extended-release, for example,formulations that only begin releasing after a fixed period of time orafter a physicochemical change has occurred, for example, then continuereleasing over an extended period.

As used herein, the term “immediate-release formulation,” is meant todescribe those formulations in which more than about 50% of activeingredient is released from the dosage form in less than about 2 hours.Such formulations are also referred to herein as “conventionalformulations.”

As used herein, the phrase “drug-release profile that is independent ofsurrounding pH” means effectively a drug composition comprising apolymeric system that is non-enteric or whose permeability andsolubility properties do not change with environmental, i.e., external,pH. Meaning, a drug composition having release characteristics such asdissolution is substantially unaffected by pH or regardless ofpH-changes in the environment. This is in comparison to a releaseprofile that is pH-dependent where the release characteristics varyaccording to the pH of the environment.

Applications

Colonic Delivery—In addition to oral delivery of small molecules andmacromolecules, including proteins, peptides, antibodies and anyfragment or otherwise modified constructs thereof, the present inventionalso has the potential to enable the development of optimized colonicdelivery of various health promoting live or attenuated organisms,including vaccines, probiotic bacteria, or genetically modifiedbacteria, modified to express and secrete therapeutic entities such asvarious interleukins.

As the colon is rich in lymphoid tissue, uptake of antigens into themast cells of the colonic mucosa produces rapid local production ofantibodies and this may be exploited through use of modifiedminicapsules to develop efficient oral vaccine delivery systems. Thiswill involve the encapsulation of antigens and adjuvants in a suitableoil, emulsion, particulate suspension or other format within minicapsulewith modified shells or shell coatings that include colon-specificpolymers and/or muco- or bio-adhesive molecules. Additionally,colon-specific lymphatic tissue targeted delivery of immunotherapeutics,including immunostimulators and immunosuppressants, is attractive as thelymphatic system acts as a reservoir or warehouse for the immune system.

Also, exploiting the lymphoid-rich colonic tissue, the present inventionwill utilize lipid-based formulations that are readily absorbed into thelymphatic vasculature and channelled toward the blood vasculatureprovides a potential means to enhance delivery of highly lipophilicdrugs or other entities, including hydrophobic peptides, proteins orother biopharmaceutical agents, including antibodies or any fragmentthereof.

It is known that certain medium and long-chain fatty acids exert anintestinal epithelial effect which leads to an increased permeability ofintestinal membranes to entities that may otherwise be impermeable orexhibit limited permeability. The medium chain triglycerides, includingbut not limited to sodium caprate, enhance absorption to a greaterextent in the small intestine than in the ileum or colon (resultsattached). In a study to investigate the effects of the long-chainpolyunsaturated fatty acids, mainly eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA) on insulin absorption from rat intestinalloops in situ, Suzuki et al demonstrated that both EPA and DHA stronglyenhanced insulin absorption and induced hypoglycaemia after rectal andcolonic dosing. DHA did not induce gross morphological changes in thestructure of the intestinal mucosa (Suzuki et al, Journal ofPharmaceutical Sciences, Vol 87, 10: Pgs. 1196-1202); 1998). Thus, it isapparent that medium chain triglycerides enhance intestinal permeabilitywhile DHA is a possible means of facilitating the intestinal absorptionof insulin and possibly other macromolecules, peptides and proteinsincluded, without inducing any serious damage to epithelial cells.Combining poorly permeable entities with medium- or long-chain fattyacids and targeted delivery to local regions of the intestine or colonhas the potential to enhance absorption of otherwise poorly permeableentities. The current invention seeks to enable such delivery throughthe encapsulation of entities formulated with polyunsaturated fattyacids using a gelling agent, including, but not limited to one or amixture of gelatine, pectin, alginate or chitosan, with or without anadditional colon-specific coating.

Thus, while the primary advantage of the current invention relates toenhanced colon delivery for absorption from the colon or treatment ofdiseased intestinal and colonic tissue, the invention also permits thedevelopment of sustained absorption of hydrophobic and lipophilic drugsthat otherwise would not be soluble in the colon. By extension, theinvention also facilitates the development of novel combinationtherapies as well as inventive chronotherapies comprising one or amultiple of drugs released at different time points.

Targeted Release/Enhanced Sustained Absorption/Reduced Side Effects

As known to those practiced in the Art, carvedilol is poorly watersoluble with highest solubility at pH 5.0, is absorbed rapidly from thesmall intestine, reaching maximum plasma concentration within two hoursand has a half-life of 7-10 hours. It undergoes extensive first-passmetabolism resulting in an absolute bioavailability of approximately25%. While a food effect is suggested, the pharmacokinetics for themarketed product, Coreg™, is linearly related to dose. It has beendemonstrated that absorption decreases within the intestine withrelative absorption in the jejunum, ileum and colon of approximately56%, 28% and 7% respectively. As a BSC Class II product, its absorptionis considered solubility limited, rather than permeability limited.Thus, a controlled release format to target initial release into thejejunum followed by release of a solubilised form of the active into thecolon is desirable for the development of a true once-daily carvedilolformulation. In the current invention, a once-daily product will bedeveloped. This will be achieved through the development of a sequentialpulsatile release minicapsule format, the core of such minicapsules willcontain carvedilol in pre-solubilised form and coated with controlledrelease polymers to ensure release two- or three-times within a 24 hourperiod, for example immediate release for intestinal absorption and 12hour-delayed release for colonic absorption. Alternatively, theimmediate release component could be formulated as solid minisphereform.

Similarly, Tacrolimus and Sirolimus are differentially absorbed from indifferent regions of the gastrointestinal tract, being optimallyabsorbed from the small intestine, with ileum and colonic absorptionefficiency dropping to half that observed for the small intestine. Also,a food effect is observed. After absorption from the gastrointestinaltract, drug effects persist for 8-12 hours after oral administration ofconventional IR tablets. The total dosage is typically in the range of2.5-10 mg per day, in exceptional cases rising to 20 mg/day. Underconventional dosage regimes, Tacrolimus is given twice daily, typicallywith one dose given before breakfast and a second dose given in the lateafternoon. Adverse effects, due to the initial rapid absorption from thesmall intestine results in above therapeutic plasma concentrations,associated with tacrolimus treatment include nephrotoxicity and thedevelopment of patient infection due to immunosuppression. There is aneed for a controlled release format that prevents toxic side effectswhile enhancing absorption from the ileum and colon. FormulatingTacrolimus in a minicapsule format, the core of which ispre-solubilised, has the potential to enhance the absorption ofTacrolimus from the colon. Also, through development of a sustainedrelease format, either through modifying the core formulation to enablesustained release or coating the surface with a sustained releasepolymer will reduce the peak plasma drug concentration, thereby reducingthe potential dose-related side effects, including nephrotoxicity andexcessive immunosuppression.

Intestinal Diseases

Gastrointestinal conditions pose a significant worldwide health problem.Inflammatory bowel diseases, which genus encompass a range of diseasesincluding Crohn's disease and ulcerative colitis, affect nearly 1million people in the United States each year. The two most commoninflammatory conditions of the intestine, ulcerative colitis (UC) andCrohn's disease (CD), are collectively known as inflammatory boweldisease (IBD). These conditions are diseases of the distal gut (lowersmall intestine, large intestine, and rectum) rather than the proximalgut (stomach and upper small intestine). Between the two, ulcerativecolitis primarily affects the colon, whereas Crohn's disease affects thedistal small intestine as well.

Inflammatory Bowel Disease (IBD)

Although they are distinct IBD conditions, the same drugs are commonlyused to treat both UC and CD. Drugs commonly used in their treatmentinclude steroids (e.g., budesonide and other corticosteroids, andadrenal steroids such as prednisone and hydrocortisone); cytokines suchas interleukin-10; antibiotics; immunomodulating agents such asazathioprine, 6-mercaptopurine, methotrexate, cyclosporine, andanti-tumor necrosis factor (TNF) agents such as soluble TNF receptor andantibodies raised to TNF; and also antinflammatory agents such as zinc.The most commonly prescribed agents for IBD include sulfasalazine(salicyl-azo-sulfapyridine, or “SASP”) and related 5-aminosalicylic acid(“5-ASA”) products, including mesalazine.

Inflammation of the ileum (the farthest segment of the small intestine)due to Crohn's disease is known as iletis. When both the small intestineand the large intestine are involved, the condition is called Crohn'senterocolitis (or ileocolitis). Other descriptive terms may be used aswell. Diagnosis is commonly made by x-ray or colonoscopy. Treatmentincludes medications that are anti-inflammatories, immune suppressors,or antibiotics. Surgery can be necessary in severe cases. Crohn'sdisease is an area of active research around the world and new treatmentapproaches are being investigated which have promise to improve thelives of affected patients.

Gastrointestinal Graft-Versus-Host-Disease (GI-GVHD)

GI GVHD is a life-threatening condition and one of the most commoncauses for bone marrow and stem cell transplant failure. Theseprocedures are being increasingly used to treat patients with leukemiaand other cancers to eliminate residual disease and reduce thelikelihood of relapse. Unlike solid organ transplants where thepatient's body may reject the organ, in GVHD it is the donor cells thatbegin to attack the patient's body—most frequently the gut, liver andskin. Patients with mild-to-moderate GI GVHD typically develop symptomsof anorexia, nausea, vomiting and diarrhea. If left untreated, GI GVHDcan progress to ulcerations in the lining of the GI tract, and in itsmost severe form, can be fatal. Systemic immunosuppressive agents suchas prednisone, which are the current standard treatments for GI GVHD,are associated with high mortality rates due to infection and debility.Further, these drugs have not been approved for treating GI GVHD in theU.S. or European Union, but rather are used off-label as investigationaltherapies for this indication.

Minicapsule-enabled colon-targeted immunosuppressant therapy deliveringagents such as cyclosporine A to the colon is a novel oral, locallyacting active therapy which will reduce the need for systemicimmunosuppressive drugs such as prednisone, which is currently used toprevent and control GI GVHD. Drugs such as prednisone have the unwantedand potentially dangerous side effects of weakening the patient's immunesystem leaving them susceptible to opportunistic infections as well assubstantially inhibiting the intended anti-cancer effect of bone marrowand stem cell transplants. Minicapsule-enabled colon-targetedimmunosuppressant therapy is designed to reduce the need for systemicimmunosuppressive drugs and thereby improve the outcome of bone marrowand stem cell transplantation. Therefore, it is possible that deliveryof intact peptides or proteins to the colon may be achieved.

Cyclosporine, Tacrolimus and Sirolimus are recognized, on- andoff-label, as common treatments for IBD and is widely used for thispurpose. However, cyclosporine, tactolimus and sirolimus therapycontinue to exhibit problems, including side effects to be detailedhereinafter. Additionally, both exhibit a half-life and efficacy profilethat is less than maximal, reflected in high and multiple daily doses,lower response and remission rates, and higher relapse rates, related toits site and mechanism of action and efficiency of delivery to the cellsof the distal gut. Extensive Cyclosporine and Tacrolimus absorption fromthe small intestine reduces its availability at distal sites in the gut,which are the sites of the therapeutic effect and the preferred sites ofdelivery, thereby necessitating high doses to be administered. Ideally,the compound should reach the distal gut (ileum and/or colon) inunchanged form, but not be absorbed into the systemic circulation as theparent compound from there. The absorption into the systemic circulationfrom proximal and/or distal sites as the parent compound results in sideeffects associated with the absorbed drug and its systemic effects.Existing oral dosage forms of cyclosporine and tacrolimus, namely softor hard gelatine capsules, are unsuited to controlled or ileum/colontargeted release.

To overcome systemic side effects and the need to administer high dosesfrequently, the current invention proposes first formulating eitherCyclosporine or Tacrolimus as solubilised formulations, encapsulatingwith a gelling agent to produce minicapsules. The encapsulating agentmay contain controlled release polymers that release only in the ileumor colon or may be coated with a polymer or other coating that resultsin same. The advantages are several-fold, including: reduced systemicabsorption of the active cyclosporine or tacrolimus which is known toresult in dose related toxicities, including nephrotoxicity, release ofsufficient dose of cyclosporine or tacrolimus in soluble form as well asa broad distribution of cyclosporine or tacrolimus throughout the colon.Furthermore, incorporating a mucoadhesive into the encapsulating shellor coating the encapsulating shell with a mucoadhesive may ensure thatthe minicapsules are in contact with the colonic mucus layer prior toreleasing the active proximal to the diseased tissue. For certainCrohn's Disease sub-groups it may be required to enable releasethroughout the gastrointestinal tract, including the small intestine.Likewise for GI-GVHD, it may be beneficial to have sustained releasethroughout the entire gastrointestinal tract from small intestine tocolon.

Propyl and asparaginyl hydroxylase inhibitors are key oxygen-sensingenzymes that confer hypoxia sensitivity to key transcriptionalregulatory pathways, including HIF-1 and NFκB. Knockout of either HIF or(IKκB-dependent) NFκB pathways in intestinal epithelial cells promotesinflammatory disease in murine models of colitis. Both HIF1 and NFκBpathways are repressed by the action of hydroxylases through thehydroxylation of key regulatory molecules.

Cummins et al. (Cummins et al. Gastroenterology 2008) demonstrated thatdimethyloxalglycine (DMOG) induces both HIF1 and NFκB activity incultured intestinal epithelial cells and is profoundly protective indextran-sodium sulphate-induced colitis in a manner that is at least inpart reflected by the development of an anti-apoptotic phenotype, whichmay reduce epithelial dysfunction.

A downside of propyl- and asparaginyl hydroxylase inhibitors ispotential pro-angiogenic and anti-apoptotic activity, which systemicallymay lead to unwanted side effects. Therefore, a delivery system thatwould delivery propyl- and asparaginyl hydroxylase inhibitors such as,but not limited to, DMOG, hydralazine, FG-4095 and derivatives thereof,to the local diseased gastrointestinal epithelial cells in lower,possibly sub-toxic concentrations is highly desirable. Furthermore,local ileum or colonic delivery may reduce systemic absorption, therebyfurther reducing the risk of side effects.

The current invention enables the targeted release of propyl- andasparaginyl hydroxylase inhibitors to the disease colonic tissue and hasresulted not only in demonstrated reduced colonic inflammation, but mayalso reduce the systemic concentration of such inhibitors leading tolimited side effects. Additionally the invention allows for targetedrelease of Inhibitor of nuclear factor kappa B kinase beta subunitinhibitors or NFkB activators.

Other immunosuppressants could be considered, either alone or incombination with cyclosporine A or tacrolimus or derivatives thereof.This include, but are not limited to, various glucocorticosteriods;cytostatics such as methotrexate and azathioprine; antibodies such asthe T-cell receptor directed anti-CD3 OKT3; the immunophilin receptorbinder sirolimus; interferons; opioids; TNFα-binding proteins,including, but not limited to, infliximab, etanercept, adalimumab,cucumin and catechins; and Mycophenolate Mofetil acid acts as anon-competitive, selective and reversible inhibitor of inosinemonophosphate dehydrogenase.

Additional therapeutics with potential for the treatment of inflammatorybowel disease or irritable bowel syndrome include, but are not limitedto, pharmaceutical compositions comprising a dose of an NO donor, suchas, but not limited to, N005[3-(2-hydroxy-1-(methylethyl)-2-nitrosohydrazino)-1-propanamine], NOC12[N-ethyl-2-ethyl-hydroxy-2-nitrosohyrdrazino-ethanamine], nitroglycerineor other therapeutics modified to include a conjugated NO donor.

Yet other pharmaceutical compositions include various calcium channelblockers, including but not limited to nimodipine, amlodipine,verapamil, including various enantiomers and salts thereof as well as NOdonor conjugates thereof. Certain natural extracts, including Neem oil,aloe vera, tripala, tumeric and other essential oils, including theomega polyunsaturated oils such as EPA, DHA, conjugated linoeic acid(CLA) and other derivatives thereof, have potential as treatments toalleviate or prevent inflammatory bowel disease as well as otherintestinal disorders, including gastric, duodenal and intestinal ulcers.Additionally, certain plant extracts, including berry extracts such asblueberry, achi, resorcinolic/phenolic lipids, resveratrol, flavanoidsand derivatives thereof, alone or in combination, have potentialapplication in IBD and IBS and other intestinal or systems conditions.The mode of action of berry extracts, such as blueberry extract, remainsuncertain but has effect on intestinal motility, stool formation andcolonic flora. Yet other potential therapeutics include, but are notlimited to, proteins, therapeutic peptides, vaccines, antibodies orfragments thereof. Local delivery to the mucosa will overcomedegradation and ensure that a high local concentration is available toenhance therapeutic efficacy. Encapsulating any of the above, alone orin any combination, into minicapsules or minispheres and targeting therelease to areas of the intestine that are diseased provide for enhanceddisease management as well as perhaps a reduction in any potential forsystemic side effects.

As mentioned above, the following therapeutics: steroids (e.g.,budesonide and other corticosteroids, and adrenal steroids such asprednisone and hydrocortisone, administered alone or in combination witha xanthine or methylxanthine compound); cytokines such asinterleukin-10; antibiotics; immunomodulating agents such asazathioprine, 6-mercaptopurine, methotrexate, cyclosporine, andanti-tumor necrosis factor (TNF) agents such as soluble TNF receptor andantibodies raised to TNF; and also antinflammatory agents such as zincare widely prescribed. The most commonly prescribed agents for IBDinclude sulfasalazine (salicyl-azo-sulfapyridine, or “SASP”) and related5-aminosalicylic acid (“5-ASA”) products are commonly prescribed and dueto significant side-effects of some of these as well as the abovementioned therapies would benefit from targeted colonic delivery and insome cases, pre-formulated to enhance solubility or permeability.

An alternative approach to treating intestinal or colonic disease is todeliver live organisms, including various bacteria such as probiotics,to specific regions of the intestine or colon where they exertprotective or therapeutic effects. Steidler has shown that it ispossible to first develop genetically modified bacteria to produceproteins and then to target the release of such proteins, includinganti-inflammatory cytokines to regions of the gastrointestinal tractwhere they will optimally exert protective or therapeutic effects. Thisinvention can formulated the bacteria for storage stability and targetthe release of such agents to the site of optimal action.

This invention is advantageous in providing methods and formulations fortreating inflammatory bowel disease. The invention proposes deliveringeffective concentrations of pre-solubised Cyclosporine, Tacrolimus,Sirolimus, Hydralazine or DMOG to affected areas of the gastrointestinaltract, with minimized systemic absorption of parent drug. The inventionis directed to, among other things, a pharmaceutical composition foradministration to a subject in need thereof comprising a dose of anactive pharmaceutical compound, and pharmaceutically acceptable salts,esters and pro-drugs thereof, and at least one pharmaceuticallyacceptable excipient, wherein the composition exhibits localized releaseand exhibits:

For Ulcerative Colitis and Crohn's Disease—a dissolution profile, whentested in a U.S.P. Type II apparatus (paddles) at 37.degree.C. and 50rpm, in pH 6.8 buffer for the test: Up to 4 hours: less than or equal toabout 20% drug released; 6 hours: less than or equal to about 35% drugreleased; 8 hours: less than or equal to about 50% drug released; 12hours: less than or equal to about 60% drug released; 18 hours: lessthan or equal to about 75% drug released; and 24 hours: from about 25%to about 100% drug released.

For GI-GVHD—a dissolution profile, when tested in a U.S.P. Type IIapparatus (paddles) at 37.degree.C. and 50 rpm, in pH 6.8 buffer for thetest: 1 hour: less than or equal to about 20% drug released; 4 hours:less than or equal to about 35% drug released; 6 hours: less than orequal to about 50% drug released; 12 hours: less than or equal to about60% drug released; 16 hours: less than or equal to about 75% drugreleased; and 24 hours: from about 25% to about 100% drug released.

This invention relates to formulations and methods for treatinginflammatory bowel disease. The term “inflammatory bowel disease”includes, but is not limited to, ulcerative colitis, Crohn's disease andGI-GVHD. Other diseases contemplated for treatment or prevention by thepresent invention include non-ulcerative colitis, and carcinomas,polyps, and/or cysts of the colon and/or rectum. All of these diseasesfall within the scope of the term “inflammatory bowel disease” as usedin this specification, yet the invention does not require the inclusionof each recited member. Thus, for example, the invention may be directedto the treatment of Crohn's disease, to the exclusion of all the othermembers; or to ulcerative colitis, to the exclusion of all the othermembers; or to any single disease or condition, or combination ofdiseases or conditions, to the exclusion of any other single disease orcondition, or combination of diseases or conditions.

Constipation Relief

Constipation manifests in a number of disease conditions or as aside-effect of certain therapies. Certain diseases, including irritablebowel syndrome, may result in significant episodes of constipation. Ithas been well documented that many therapeutics, including, but notlimited to, opioids and antibiotics result in constipation. Opioids,including, but not limited to, morphine, morphine sulphate and thesystemically active opioids naltrexone and naloxone are widelyprescribed for the effective treatment of a myriad of conditions thatrequire pain modulation. Often, the rate limiting step to effectiveopioid treatment is constipation. To overcome constipation, a number ofapproaches have been adopted, including, but not limited to osmoticagents such as polyethylene glycol, laxatives such as the naturallyoccurring senna and bisacodyl and 5HT receptor antagonists such as the5HT4 antagonist zelnorm. While such adjuvant agents may be effective intreating these adverse effects, they are associated with additionaladverse effects and are sometimes ineffective. As an alternative, theopioid mu receptor antagonists methylnaltrexone and alminopan have shownpositive benefits in the treatment of opioid-induced constipation.

Methylnaltrexone has been in development since it was first synthesizedin 1979 to offset the constipating effect of morphine, but it is not yetapproved by the FDA for this use. By not crossing the blood-brainbarrier, methylnaltrexone is thought to counter the constipating effectsof opioids without reducing their effectiveness as pain relievers. Majorquestions remain about what dose is most effective and at what point,and how often, the drug should be given. Alminopan has reported efficacyin accelerating gastrointestinal recovery in patients undergoinglaparotomy. It is a peripherally acting mu-opioid receptor antagonistdesigned to block the adverse side effects of opioid analgesics on thegastrointestinal tract without blocking their beneficial analgesiceffects. A pooled analysis of 3 phase 3 efficacy trials assessed theeffect on opioid analgesics after surgery. Almivopan acceleratedgastrointestinal recovery while maintaining centrally mediated analgesiaas measured by opioid consumption and visual analog pain scores.

The present invention will permit the controlled release of productsthat will overcome the constipating effects of opioids. It may bebeneficial to have these products released either throughout thegastrointestinal tract or to specific locations, either to the smallintestine, the ileum or the colon. The benefits may include lower doserequirements, improved efficacy as well as ease of administration andgreater distribution of the product. In addition to overcoming theconstipating effects of opioids, the present invention may also suitother conditions such as post-operative ileus or general constipation.Potential products include controlled release osmotic agents such aspolyethylene glycol, laxatives such as the naturally occurring senna andbisacodyl, 5HT receptor antagonists such as the 5HT4 antagonist zelnormas well as the opioid mu receptor antagonists methylnaltrexone andalminopan.

There exists an unmet need for an oral dosage form that permitsonce-daily delivery of opioid-based drugs, with reduced side effects.The optimal dosage form requires that the opioid-based drug is releasedover an 18-24 hour period, is effective over a 24 hour period and doesexhibit reduced negative side effects, including constipation andpruritus.

The current invention will additionally enable the development ofcombination products, including combinations for the oral administrationof one or more pain-relieving opioids with one or more constipationrelieving agents. Specifically, the current invention proposes todevelop a controlled release morphine-based product, such as morphinesulfate, that is released over 18-24 hours, in the presence or absenceof a controlled release ion-channel inhibitor, such as, but not limitedto nimodipine, to extend the effective analgesic period, in combinationwith a controlled release opioid antagonist, such as naloxone,naltrexone or methylnaltrexone, which may be released throughout thegastrointestinal tract or only in the colon and rectum.

Oral Tolerance

The intestinal mucosal immune network has evolved an ability to maintainrelative unresponsiveness or tolerance to a wide array of antigensderived from dietary sources and commensal bacteria. This phenomenon isreferred to as oral tolerance. Friedman et al proposed that oraltolerance is mediated by the generation of active cellular suppressionor clonal anergy and that the determining factor is the dose of antigenfed orally (PNAS USA 1994; 91:6688-92). Oral tolerance is dose-specificand lose of tolerance might occur with increased dosages(Nagler-Anderson et al., PNAS USA 1986; 83:7443-6). Low dose of antigenadministration favours the induction of active cellular regulation (Chenet al., 1994 Science; 265:1237-1240). Higher doses favour the inductionof clonal anergy or deletion (Chen et al., 1995 Nature; 376:177-180). Inanother study, high doses of myelin basic protein (MBP) to mice whoseT-cells carry a T-cell receptor (TCR) specific for MBP resulted inT-cell activation and receptor downmodulation (Benson et al., 2000 JClin Invest, 106:1031-1038). Additionally, it has been shown that oraltolerance also can be enhanced by feeding immune adjuvants such aslipopolysaccharide or cholera toxin subunit B, which appear to stimulateadditional populations of cells to down-regulate immune responses(Khoury et al., J Exp Med 1992; 176:1355-64).

Oral tolerance has been shown to prevent or treat a variety of T-cellmediated autoimmune disorders. In a double-blind pilot trial involving30 patients with multiple sclerosis, oral administration of bovinemyelin antigens decreased the number of T-cells that reacted with myelinbasic protein, with no measurable toxicity (Werner et al., Science 1993;259:1321-4). Trentham et al demonstrated clinical efficacy of oraltolerance by feeding type II collagen to 60 patients with severe, activerheumatoid arthritis (Trentham et al., Science 1993; 261:1727-30). In ananimal model of trinitrobenzene sulfonic acid (TNBS), Th1-mediatedcolitis, it was reported that feeding colonic extracts haptenated withTNBS prevented the development of mucosal inflammation (Neurath et al.,J Exp Med 1996; 183:2605-16). In a Phase I study to evaluate the safetyand efficacy of autologous colonic protein extract feeding for thetreatment of moderate-to-severe Crohn's Disease, Margalit et al.demonstrated safety and induced remission in 7 out of 10 subjects (Am JGastroenterol 2006; 101). Other animal disease models, including stroke,Alzheimer's disease and atherosclerosis as well as type 1 diabetes haveresponded to mucosal administration of antigens.

To exploit oral tolerance in treating oral autoimmune or inflammatorydiseases, it will be necessary to understand the various responses thatare induced or suppressed during this process, beginning when antigenfirst encounters gut-associated lymphoid tissue (GALT), a well developedimmune network consisting of lymphoid nodules (Payer's Patches),epithelial villi, intraepithelial lymphocytes, and other lymphocytesscattered throughout the lamina propria. Antigens may act directly atthe level of the GALT or may exert their effects after absorption. Asoral tolerance and mucosal immunization are parts of one immunologiccontinuum related to antigen presenting cell interactions with T cellsin the GALT. Thus, the oral delivery of antigens will require finetuning—in addition to antigen dose, the nature of the antigen, theinnate immune system, the genetic background and immunological status ofthe host, and mucosal adjuvants will influence the immunological outcomefollowing oral antigen administration. The development of advancedorally delivered oral tolerance and mucosal immunization prophylacticsor therapies may benefit from targeted delivery to specific regions ofthe intestinal tract. The rectum/colon is a mix of immune inductive(organised lymphoid tissues) and effector sites (diffuse lamina propria)whereas the jejunum contains almost no immune inductive sites. This isreflected in the lymphoid composition of each tissue: the jejunumcontains mostly memory CD4⁺ T cells, while the colon contains a largerproportion of naïve CD4⁺ T cells (Veazey and Lackner, 2006; PLoSMedicine; 3:12-2188-9). Thus, it could be hypothesised that duringnormal ingestion that peptides and proteins are so degraded when theyreach the colon they no longer activate an immune response in naïve CD4⁺T cells.

The present invention will enable the development of formulationscomprising the necessary antigenic, including any covalently ornon-covalently modified, peptides to be formulated, with or withoutadjuvants or permeability enhancers, and to be encapsulate within singleor multiple layer, with the layers or polymer coatings of which beingmodified to ensure release at the most appropriate location along theintestine or colon/rectum. The result will be an optimized, tunable andmodular orally administered oral tolerance or mucosal immunizationdelivery technology. In addition to the above mentioned diseases thathave been explored, the current invention may also benefit broaderapplications, such as, but not limited to, celiac disease, foodallergies and more general allergies.

HIV Small Molecule Treatment and Vaccine

In acute HIV infection, a rapid and profound loss of CD4⁺ CCR5⁺ T cellswithin days of infection, whereas peripheral lymphoid tissues such asblood and lymph nodes, which harbour mainly naïve CD4⁺ T cells, are lessseverely affected (Brenchley et al., 2004 J Exp Med 200:749-759). Thisrecognition of the mucosal immune system as a principal target of earlyHIV infection has implications for vaccine development. Furthermore,Mehandru et al. studying lymphocyte populations from the intestine andperipheral blood were obtained from recently HIV-infected patients aswell as uninfected volunteers demonstrated that most patients whoinitiate high activity anti-retroviral therapy (ART) as early aspossible after HIV infection still do not experience completerestoration of intestinal CD4⁺ T cells to baseline levels, regardless ofthe duration of therapy. Instead, HIV infection results in a continuousstate of activation in the intestinal immune system that is notreflected in peripheral lymphoid tissues (Mehandru et al., 2006; PLoSMed 3(12): e484). The data from Mehandru et al. provide evidence thatintestinal inflammation and continual infection, destruction, andturnover of CD4⁺ T cells occur in patients on ART. This would suggestthat drugs with better intestinal tissue distribution, together with,perhaps, mechanisms to reduce or prevent immune activation in mucosaltissues may more effectively combat HIV infection.

The current invention will permit a number of approached to theprevention and treatment of HIV/AIDS, including controlled release ofARTs along the entire intestinal and colonic/rectal tract or topre-specified sites along same. In addition, the current invention willpermit the development of oral tolerance as well as intestinal/colonicmucosal vaccines or immunotherpeutics approaches. Furthermore, with thecurrent invention, a combination ART/immune system modulation approachis possible.

Tight Junction Modulators

A number of small molecule and peptides are in development to regulatethe functional state of tight junctions (TJ) and paracellularpermeability. Molecules that transiently and reversibly open the TJs ofepithelial and endothelial tissues such as the intestinal mucosa, bloodbrain barrier and pulmonary epithelia. As increased paracellularpermeability is implicated as a causal factor in many disease states,modulation of permeability by TJ regulatory pathways represents a veryimportant therapeutic opportunity. Potential applications range from thetreatment of diseases involving tight junction dysfunction andautoimmunity to vaccine and drug delivery. Certain TJ modulators such,but not limited to, parozotide acetate, have potential in the treatmentof gastrointestinal disorders, including Celiac Disease and InflammatoryBowel Disease. The current invention will permit the local delivery oftight junction modulators and thus enhance the utility of such agents inthe treatment of a range of diseases or to promote the induction ofmucosal or systemic immunity to enable the development of oral vaccinesor oral tolerance approaches.

Anti-Allergenic Therapeutics

It has been proposed by the so-called hygiene hypothesis that modulationof the immune system by infection with helminth parasites, includingschistosomes, reduces the levels of allergic responses in infectedindividuals. This hypothesis proposes that a shift in the immune systemtoward type 1 immunity upon early exposure to infections such asbacterial and viral infections protects against allergic diseases byreducing the expression of Th2 cytokines generally evoked by allergens.An alternative explanation holds that certain parasitic helminthinfections may protect against allergic disorders because humanpopulations with high rates of parasitic helminth infections, whichinduce an immunological shift toward the “allergic” Th2 responses, havea reduced prevalence of allergic disorders. Schistosoma spp. aretropical helminth parasites, characteristically associated with beingpotent inducers of Th2 cytokine responses including eosinophilia and IgEresponses, that have been postulated to ameliorate atopic disorders inhumans (The Journal of Immunology, 2004, 173: 6346-6356).

Circumstantial evidence suggests that Schistosoma spp, tropical helminthparasites, ameliorate atopic disorders in humans. Schistosomes arecharacteristically associated with being potent inducers of Th2 cytokineresponses, including eosinophilia and IgE responses. Despite Th2responses being considered necessary for the development of allergies,the presence of schistosome infections in humans may reduce allergicresponses in infected populations.

To confirm the hygiene hypothesis, Schistosoma hematobium-infectedschool children in Gabon had a lower prevalence of skin reactivity tohouse dust mites than those free of this infection. Therefore, it hasbeen proposed that chronic down-regulation of the immune system duringhelminth infection evokes a regulatory environment that may impartprotection from allergies.

Bashir et al. have demonstrated a role for experimental helminthinfection in protection against the development of allergy in mice(Bashir et al. (2002) J. Immunol. 169:3284). They assessed the effect ofTh2 responses induced by the intestinal helminth infection (H.polygyrus) on the development of an allergic response to the foodallergen peanut Ag, with protection being mediated at least in part bythe production of IL-10.

Although a novel mechanism by which a helminth parasite can preventanaphylaxis in mice has been demonstrated, it may be too simplistic toenvisage a common mechanism by which different helminth parasites mayprevent allergic responses. Infection of mice with a gastrointestinalnematode (H. polygyrus) has been shown to reduce allergic responses inone study, whereas in a separate study mice infected with anothergastrointestinal nematode (Trichinella spiralis) had exacerbatedanaphylaxis (Strait et al., 2003, J. Immunol. 170:383.). Therefore, itis suggested that there are defined differences in the infectivity andimmunity of these two parasites as well as in the allergy models usedthat could explain the differences between the studies.

Fallon's laboratory has demonstrated that S. mansoni infection protectsmice from an experimental model of systemic fatal anaphylaxis, with theworm stage of infection being shown to mediate this protective effect.In this study it was demonstrated that mice infected with S. mansoni arerefractory to experimental systemic anaphylaxis. It was established thatit is the worm stage of infection that elicits the protective phenotypein this model, with worm-infected mice completely protected againstanaphylaxis, whereas worm egg-infected mice were only partiallyprotected. We have identified that schistosome worm infection of miceprevents anaphylaxis via a B cell- and IL-10-dependent mechanism. (TheJournal of Immunology, 2004, 173: 6346-6356).

Asthma is an atopic inflammatory disorder of the airways that ischaracterized by increased airway hyperresponsiveness (AHR), eosinophilinfiltration of the airways, and mucus hypersecretion that results inintermittent airway obstruction. The immune etiology of asthma iscomplex, but genetic and immunological analyses of atopic individualshave revealed that Th2-type cytokines are causally associated withallergies with a type 2 cytokine response being characterized byincreased (Th2) cell development and production of IL-4, -5, -9, and -13resulting in IgE production, mucus hyperplasia, and eosinophilia.

Fallon's laboratory demonstrated that Schistosoma mansoni infectionprotects mice from anaphylaxis through a regulatory mechanism induced bythe worm. In a study to evaluated whether S. mansoni infection of mice,the mouse being the preferred animal model for studies on theimmunobiology of schistosomiasis, altered susceptibility of the animalsto OVA-induced AHR, which is also widely used as a model of humanpulmonary inflammation. It was demonstrated that the worm stage of S.mansoni infection modulates mice so they are refractory to AHR. This isthe first formal demonstration of a mechanism that human parasitic wormsuse to suppress allergen-induced airway inflammation.

The present invention will permit the development of formulationscontaining whole or fragments of parasites, including helminth wormssuch as Schistosoma mansoni, and the gastrointestinal nematode H.polygyrus, including any covalently or non-covalently modified formatsthereof to be formulated, with or without adjuvants or permeabilityenhancers, and to be encapsulate within single or multiple layer, withthe layers or polymer coatings of which being modified to ensure releaseat the most appropriate location along the intestine or colon/rectum.The result will be an optimized, tunable and modular orally administeredanti-allergenic delivery technology. In addition to the above mentioneddiseases that have been explored, the current invention may also benefitbroader applications, such as, but not limited to, asthma, celiacdisease, food allergies and more general allergies.

Targeted Delivery of Conjugated Linoleic Acid (CLA)

Conjugated linoleic acid (CLA) is a collective term used to describe oneor more positional and geometric isomers of linoleic acid, an essentialfatty acid. Recent attention focused on CLA can be explained by theplethora of potential health benefits attributed to this unique fattyacid.

Dairy products and other foods derived from ruminant animals are themain dietary sources of CLA. The cis-9, trans-11 isomer is thepredominant biologically active CLA isomer in bovine milkfat and in theoverall diet of humans. Biological activity for other isomers,particularly the trans-10, cis-12 isomer, has recently beendemonstrated.

A variety of factors, such as the diet, can influence the CLA content ofmilkfat. Because the CLA content of dairy products is related to theirfat content, CLA levels are greater in higher fat than in lower fatproducts. The finding that various dietary manipulations can increasethe CLA content of milkfat may open the door for CLA-enriched dairyfoods.

In vitro and experimental animal studies document a growing number ofpotential health benefits for CLA. These include: AnticarcinogenicEffects—CLA inhibits the proliferation of some cancers such as mammary,colorectal, prostate, and stomach cancers. Virtually all studies haveused synthetic mixtures of CLA. For the first time, an anticarcinogeniceffect has been demonstrated for naturally-occurring CLA in food(butter); Antiatherogenic Effects—CLA lowers total and LDL cholesterolas well as triglyceride levels and reduces the severity ofatherosclerotic lesions in the aortas of experimental animals; BodyComposition Changes—Intake of CLA reduces body fat and increases leanbody mass in several species of growing animals; Enhanced ImmuneFunction—CLA enhances select immune responses in experimental animals,while at the same time protecting against immune-induced cachexia orbody wasting; Increased Bone Formation—CLA intake by growing animalsincreases the rate of bone formation by influencing factors thatregulate bone metabolism; and Anti-Diabetic Effects—CLA improves glucoseutilization and reverses symptoms of diabetes in laboratory animalsgenetically at risk for this disease.

Much remains to be learned about the underlying mechanism(s) by whichCLA exerts its diverse physiological effects. A variety of mechanismsare likely to be involved. The wide spectrum of CLA's biological effectsmay be explained, in part, by the unique biological effects of specificCLA isomers. Although the cis-9, trans-11 CLA isomer appears to beresponsible for a number of the potential health benefits attributed toCLA, new findings indicate that CLA's effects on lipid metabolism andbody composition are due largely to the trans-10, cis-12 isomer.

The present invention will permit the development of formulationscontaining CLA or fractions or derivatives thereof, including anycovalently or non-covalently modified formats thereof to be formulated,with or without adjuvants or permeability enhancers, and to beencapsulate within single or multiple layer, with the layers or polymercoatings of which being modified to ensure release at the mostappropriate location along the intestine or colon/rectum. The resultwill be an optimized, tunable and modular orally administered product toenhance systemic absorption for systemic therapeutics or delivered tospecific regions of the GIT to treat local intestinal or colonicdiseases.

The present invention provides a multiple minicapsule modified releasecomposition comprising at least one population of activeingredient-containing minicapsules which, upon administration to apatient, exhibits a single, bimodal or multimodal release profilethroughout the entire gastrointestinal tract or at pre-specified regionsalong the gastrointestinal tract.

The multiple minicapsule or minisphere modified release composition maycomprise at least two populations of active ingredient-containingminicapsules which, upon administration to a patient, exhibits a bimodalor multimodal release profile that results in a plasma profile withintherapeutically effective pharmacokinetic parameters.

In one case the invention provides a multiple minicapsule modifiedrelease composition comprising at least two populations of activeingredient-containing minicapsules which, upon administration to apatient, exhibits a pulsatile release profile.

In another case the invention provides a multiple minicapsule modifiedrelease composition comprising at least two populations of activeingredient-containing minicapsules which, upon administration to apatient, results in a pulsatile plasma profile.

The invention also provides a multiple minicapsule modified releasecomposition comprising at least two populations of activeingredient-containing minicapsules which, upon administration to apatient, produces a plasma profile substantially similar to the plasmaprofile produced by the administration of two or more IR dosage formsgiven sequentially.

The invention also provides a multiple minicapsule modified releasecomposition comprising at least two populations of activeingredient-containing minicapsules in which the amount of the one ormore active ingredients in the first population of minicapsules is aminor portion of the amount of the one or more active ingredients in thecomposition, and the amount of the one or more active ingredients in theone or more additional population of minicapsules is a major portion ofthe amount of the one or more active ingredients in the composition.

In another aspect the invention provides a multiple minicapsule modifiedrelease composition wherein each minicapsule contains one or more activeingredient combined in the minicapsule core, shell or coating orseparately present in each to enable a sustained or zero-orderpharmacokinetic profile through modification of the core formulation,the shell or minicapsule coating.

The invention further provides a multiple minicapsule modified releasecomposition comprising at least two populations of different activeingredient-containing minicapsules in which the two or more actives arereleased concomitantly.

Alternatively, the invention provides a multiple minicapsule modifiedrelease composition comprising at least two populations of differentactive ingredient-containing minicapsules in which the two or moreactives are released sequentially.

Yet another object of the invention is to provide a multiple minicapsulemodified release composition to protect an acid-labile.

The invention provides a multiple minicapsule modified releasecomposition to protect or degradative-enzyme sensitive activeingredients and to release such proximal to the intestinal epithelialcell wall or in the colon, in the lumen or proximal to the epithelialwall in the small intestine or colon.

In one case the invention provides a multiple minicapsule modifiedrelease composition whereby the active or actives are released in theileum or colon, where the active is not absorbed but may yet be locallyactive.

In the invention the minicapsule core composition may include excipientsin a liquid form that permit controlled or sustained release inconjunction with or independent of the shell or coating. Such forms caninclude various matrix structures or melt-extruded polymers ortemperature modulated lipid-based excipients, including, but not limitedto the Gattefosse Gelucire® range of saturated triglycerides or theSasol range of Witepsol® saturated triglycerides which demonstrateconsiderable sustained release when exposed to the gastrointestinalenvironment.

The minicapsule core composition may include excipients in a semi-liquidor solid form that permit controlled or sustained release in conjunctionwith or independent of the shell or coating or where the core comprisesthe entire minicapsule or minisphere.

The pharmaceutically acceptable excipient may be chosen from carriers,fillers, extenders, binders, humectants, disintegrating agents,solution-retarding agents, absorption accelerators, wetting agents,absorbents, lubricants, stabilizers, coloring agents, buffering agents,dispersing agents, preservatives, organic acids, and organic bases.

The modified-release compositions of the invention may comprise animmediate-release core and a semi-permeable membrane. In someembodiments, the modified-release compositions of the invention maycomprise a modified-release semi-solid core and a semi-permeablemembrane.

The present invention also provides sustained release of drugs thatotherwise are readily absorbed in the small intestine but exhibitlimited colonic absorption is made possible through targeted release offormulations wherein the drug or other entity is pre-solubilised.Examples of such drugs include tacrolimus, carvedilol, cyclosporine andlosartan.

The present invention allows for sustained release of carvediolconcomitantly or sequentially with hydralazine for the treatment ofcertain cardiovascular conditions, including, but not limited tocongestive heart failure, essential hypertension or others.

The present invention provides sustained release formulations ofcarvediol concomitantly or sequentially with hydralazine for theprevention or to reduce risk of certain cardiovascular conditions,including, but not limited to congestive heart failure, essentialhypertension or others.

The present invention also permits development of sustained releasetacrolimus or cyclosporine in combination with an antioxidant or nuclearfactor kappa B inhibitor such as, but not limited to curcuminoids, suchas, but not limited to curcumin, to reduce nephrotoxicity or increaseeffectiveness in treating inflammatory bowel disease or to enhanceefficacy in the treatment of diabetes-related kidney disorders.

The present invention also permits development of sustained releasetacrolimus, sirolimus cyclosporine in combination with mycophenolatemotefil and/or other immunomodulators to enhance the management ofpost-transplant treatment.

The invention also includes methods of treating inflammatory boweldisease comprising administering to a subject in need thereof apharmaceutical composition comprising a dose of a cyclosporine,sirolimus or tacrolimus, or pharmaceutically acceptable salts, estersand pro-drugs thereof, and at least one pharmaceutically acceptableexcipient. Such formulations are preferentially developed to ensurerelease in the ileum and/or colon.

Yet another embodiment of this invention relates to methods of treatinginflammatory bowel or irritable bowel syndrome disease comprisingadministering to a subject in need thereof a pharmaceutical compositioncomprising an effective hydroxylase inhibitor, including PHD inhibitorsand asparaginyl hydroxylase inhibitors, such as but not limited toHydralazine, DMOG or others and or covalent or non-covalent modifiedactive or inactive entities, including nitric oxide donors (NO-donors).

Still another embodiment of this invention relates to methods oftreating inflammatory bowel or irritable bowel syndrome diseasecomprising administering to a subject in need thereof a pharmaceuticalcomposition comprising an effective calcium channel blocker, such as butnot limited to nimodipine, verapamil, including various salts andenantiomers thereof or covalent or non-covalent modified active orinactive entities, including nitric oxide donors (NO-donors).

Another embodiment of this invention relates to methods of treatinginflammatory bowel disease or irritable bowel syndrome comprisingadministering to a subject in need thereof a pharmaceutical compositioncomprising activators of Nuclear Factor Kappa B (NFκB), including, butnot limited to, DMOG, Hydralazine, BAY 117082, Curcumin or others and/orcovalent or non-covalent derivatives, including but not limited to,covalently attached nitric oxide donor groups, thereof, which also mayinhibit apoptosis, with release of same targeted to the ileum or colon.

Still another embodiment of this invention relates to methods oftreating inflammatory bowel disease comprising administering to asubject in need thereof a pharmaceutical composition comprisingTacrolimus or Cyclosporine A and a curcuminoid, such as, but not limitedto, curcumin, with release of same targeted to the ileum or colon.

Yet another embodiment of this invention relates to methods of treatinginflammatory bowel disease comprising administering to a subject in needthereof a pharmaceutical composition comprising a TNFα inhibitor,including small molecules as well as antibodies or otherbiopharmaceuticals and/or covalent or non-covalent derivatives thereofwith release of same targeted to the ileum or colon.

One more embodiment of this invention relates to methods of treatinginflammatory bowel disease or irritable bowel syndrome comprisingadministering to a subject in need thereof a pharmaceutical compositioncomprising a kappa B alpha (IKκBα) kinase inhibitor and/or covalent ornon-covalent derivatives thereof with release of same targeted to theileum or colon.

Yet another embodiment of this invention relates to methods of treatinginflammatory bowel disease or irritable bowel syndrome comprisingadministering to a subject in need thereof a pharmaceutical compositioncomprising nicotine and/or derivatives thereof with release of sametargeted to the ileum or colon.

Yet another embodiment of this invention relates to methods of treatinginflammatory bowel disease or irritable bowel syndrome comprisingadministering to a subject in need thereof a pharmaceutical compositioncomprising a dose of an NO donor, such as, but not limited to, N005[3-(2-hydroxy-1-(methylethyl)-2-nitrosohydrazino)-1-propanamine], NOC12[N-ethyl-2-ethyl-hydroxy-2-nitrosohyrdrazino-ethanamine], nitroglycerineor other therapeutics modified to include a conjugated NO donor.

Another embodiment of the present invention relates to targeted deliveryof natural plant, marine or other extracts, including essential oilssuch as Neem, aloe vera and the omega range of polyunsaturated oils,including EPA, DHA and CLA, with or without plant extracts such as, butnot limited to, berry extracts, tripala, tumeric, resveratrol,resorcinolic/phenolic lipids, flavanoids and any natural or syntheticderivatives thereof.

Another embodiment of the present invention relates to a pharmaceuticalcomposition comprising a combination of any of the above examplesreleased anywhere along the gastrointestinal tract.

In another embodiment, this invention relates to methods of treatingother colonic diseases, including, but not limited to, carcinomas,polyps, and/or cysts of the colon and/or rectum comprising administeringto a subject in need thereof a pharmaceutical composition comprising adose of a COX-II inhibitor, such as, but not limited to, Celebrex or anantimetabolite such as Methotrexate.

In an additional embodiment of the present invention, targeted releaseof formulations of small molecules or macromolecules, including vaccinesand immunotherapeutics, that are preferentially absorbed by lymphoidtissue in the colon or elsewhere in the gastrointestinal tract isincluded.

A further embodiment of the present invention, targeted release offormulations to treat liver cirrhosis or other fibrosis-relatedconditions, including calcium channel blockers such as, but not limitedto, nifedipine or hydroxylase inhibitors, such as, but not limited to,hydroxylase or nitric oxide donors or derivatives thereof, administeredsingly or in combination. Such active agents may be formulated withentities that preferentially target the liver, including conjugatedcyclodextrins or derivatives thereof.

Yet another embodiment is the co-administration of immediate releaseproximal tubule diuretics and delayed release distal tubule diuretics,such as, but not limited to mannitol, acetazoloamide, furosemide,spironolactone, amiloride, triamterene, butnetanide, ethacrynic acid, orthiazides for the treatment of hypertension and other nephron-relateddisorders.

An additional embodiment of the invention is a single or combinationproduct to treat diabetes or complications associated with diabetes thatincludes one or other of insulin, insulin sensitizers, sulphonamides,glucagons-like peptides or the like, released concomitantly orsequentially as required.

One other embodiment of the invention is a single or combination productto treat one or more cardiovascular disease that comprises apharmaceutical formulation comprising one or other of a statin, a bileacid sequestrant, a cholesterol absorption inhibitor, a lipid absorptioninhibitor, an antioxidant, aspirin, a fibrate, an ACE inbibitor, an ATIIreceptor inhibitor, a nitric oxide donor, a beta blocker, a calciumchannel blocker and so on, released concomitantly or sequentially asrequired.

Still a further embodiment of this present invention is targetedgastrointestinal release of formulations containing antibodies,including fragments thereof, to maximize systemic bioavailability orenhanced local intestinal efficacy.

Still an additional embodiment of this present invention is targetedgastrointestinal release of formulations containing nucleic acidtherapeutics, including antisense oligonucleotide, siRNAs and genetherapy constructs, to maximize systemic bioavailability or enhancedlocal intestinal efficacy.

Still an additional embodiment of this present invention is targetedgastrointestinal release of formulations containing peptides, proteinsor carbohydrates, including modified or conjugated constructs, tomaximize systemic bioavailability or enhanced local intestinal efficacy.

Another embodiment of the current invention relates to non-covalentcomplexion of a drug with a carrier such as cyclodextrins,maltodextrins, dextrins or modifications thereof and targeting therelease of such to the specific sites along the gastrointestinal tract.

Another particular embodiment of the present invention relates to smallmolecules or biopharmaceutical molecules, which may include siRNAconstructs, which have been conjugated to entities that serve either toenhance stability and/or increase the hydrophilic nature of the activedrug molecule and targeted in the release of such conjugates to thesmall intestine or colon.

Specifically, another embodiment of the present invention relates tosmall molecules or biopharmaceutical molecules, which may include siRNAconstructs, to which lipophilic entities have been conjugated to enhancestability and/or increase intestinal wall permeability and to targetsuch conjugated drugs to specific sites along the gastrointestinal tractto maximise absorption for enhances systemic efficacy or to maximiselocal intestinal activity.

Yet a further embodiment of the present invention is targetedgastrointestinal release of formulations containing conjugated drugs,the conjugation which prevents absorption into the systemic or lymphaticvasculature yet retains local intestinal therapeutic efficacy.

Still a further embodiment of the present invention is targetedgastrointestinal release of formulations comprising poorly solubleactives, including small molecules and biopharmaceuticals formulatedwith amongst other excipients, permeability enhancers, such as, but notlimited to, sodium dodecanoate (C12), Sodium Caprate (C10) and/or SodiumPalmitate (C16).

One more embodiment of the present invention is targetedgastrointestinal release of formulations containing live or liveattenuated organisms, including bacteria or genetically modifiedbacteria and/or live or live-attenuated viruses.

In the current invention, in the development of treatments forinflammatory bowel disease, the active pharmaceutical ingredient isinterchangeable, including any one or combination of cyclosporine A,tacrolimus, sirolimus, hydralazine, DMOG, proply- and/or asparaginylhydroylase inhibitors, EPA, DHA, natural plant extracts, natural marineextracts or other biological and active entities, which may includesiRNA constructs.

In the current invention, in the development of treatments forGraft-Versus-Host Disease, the active pharmaceutical ingredient isinterchangeable, including any one or combination of cyclosporine A,tacrolimus, sirolimus, EPA, DHA, natural plant extracts, natural marineextracts or other biological and active entities, which may includesiRNA constructs.

In the current invention, the immunological modulating entities,including antigens, adjuvants, emulsions, oils, and small molecules areinterchangeable and may be utilised for the development of vaccines,oral tolerance modulators and allergen modulators, which may includesiRNA constructs.

The invention allows for the development of solid-, semi-solid orliquid-filled minicapsules comprising one or more layer and producedusing conventional seamless minicapsule processes, modified meltextrusion, non-pareil coating, non-pareil drug layering or otherprocesses that enable the production of the desired dosage form.

The invention allows for a broad range of controlled release polymercoatings to be applied. Coating materials may include any combination ofthe commercially available acrylic-, methacrylic-, ethylcellulose-basedpolymers (such as, but not limited to the Eudragit™ and Surelease®range), as well as other polymers with natural polysaccharides,including, but not limited to amylose, pectin, alginate, amylopectin,chitosan, galactomannan, guar gum and any derivatives thereof, has thepotential to customise how, where and when drugs are released from theunderlying or embedded solid, semi-solid or liquid forms. In allexamples cited in this specification, any specific polymer may beinterchanged or combined with any other polymer to enable the requiredrelease profile according to the preferred optimal therapeutic outcomeenvisaged.

The invention provides a solid oral dosage form comprising the multipleminicapsule modified release composition of the present invention, thesaid minicapsules being one layer or multiple layer. Where a two layerminicapsule has a shell comprised of a gelling agent with a controlledrelease polymer or other coating or comprised of controlled releasepolymer or other materials.

The invention also provides a sachet format comprising multipleminicapsule modified release composition of the present invention forease of administration to paediatrics, geriatrics or other patientpopulations with swallowing difficulties.

The invention will be more clearly understood from the followingexamples.

EXAMPLES

The FIGS. 1 to 4 schematically illustrate the various minicapsule orminisphere forms that the present invention uses. Active drug substancesmay be formulated using one or more populations of such minicapsule orminisphere structures.

FIG. 1—Liquid-filled minicapsule with controlled release polymercoatings. This format comprises an active substance encapsulated using asuitable gelling agent that is further coated to permit controlled ortargeted release along the gastrointestinal tract. The active substanceis in an enhanced solubilised or permeabilised form. The open arrowrepresents the release of a drug molecule into the external medium,where it is fully soluble when released (Referred to as Format 1);

FIG. 2—Semi-solid- or solid-filled minicapsule/minisphere withcontrolled release polymer coatings. This format comprises an activesubstance, liquid at processing temperature, encapsulated using asuitable gelling agent that is further coated to permit controlled ortargeted release along the gastrointestinal tract. The active substanceis in an enhanced solubilised or permeabilised form. The open arrowrepresents the release of a drug molecule into the external medium,where it is fully soluble when released (Referred to as Format 2);

FIG. 3—Gelling agent encapsulating enhanced solubilised or permeabilisedactive substances, including substances in micronised or nanonised form,either crystalline or amorphous formats. The resulting solid sphericalstructures may be further coated to permit controlled or targetedrelease along the gastrointestinal tract. The open arrow represents therelease of a drug molecule into the external medium, where it is fullysoluble when released (Referred to as Format 3);

FIG. 4—Active substances, in crystalline or amorphous form, blended withextrudable or other polymers which are melt-extruded, drug layered,spheronised or otherwise produced which may be further coated to permitcontrolled or targeted release along the gastrointestinal tract or,alternatively, are inherently controlled release. The open arrowrepresents the release of a drug molecule into the external medium,where it is fully soluble when released (Referred to as Format 4).

Example 1

As per FIG. 1 above, Example 1 represents a controlled releaseliquid-filled minicapsule of the Format 1 variety. The core formulationwas prepared as follows. Tacrolimus was dissolved in a suitable volumeof ethanol. Once dissolved, the solution was blended with a suitable mixof Labrafil and Olive oil. The shell solution was prepared as follows:Appropriate quantities of gelatin and sorbitol were added to water andheated to 70 degrees C. until in solution. The minicapsules wereprepared using a Spherex Labo to produce 2-layer minicapsules, the coreof which comprises Tacrolimus in an enhanced solubilised andpermeabilised formulation. In addition, the core formulation does enablea degree of sustained release.

TABLE 1 Once-daily Tacrolimus Ingredients % w/w Core CompositionTacrolimus 3.25 Labrafil 36.4 Olive Oil 47.65 Ethanol 12.7 ShellComposition Gelatin 90.0 Sorbitol 10.0

Example 2

Tacrolimus release from uncoated minicapsules of Example 1 (Format 1):Dissolution profiles in FIG. 5 demonstrate the following release oftacolimus from minicapsules expressed as a percentage of the totalminicapsule content: less than 55% within 1 hr; less than 80% within 4hrs; less than 90% within 12 hrs and less than or equal to 100% at 24hr.

Example 3

Tacrolimus release from minicapsules of Example 1 (Format 1) coated with12.5% weight gain Eudragit™ RS30D followed by 25% weight gain Eudragit™FS30D: Dissolution profiles in FIG. 6 demonstrate the following releaseof tacolimus from minicapsules expressed as a percentage of the totalminicapsule content: less than 10% within 1 hr; less than 30% within 4hrs; less than 75% within 12 hrs and less than or equal to 100% at 24hr. This is suited either to a once-daily systemic absorption product oran ileum/colon-specific product.

Example 4

Tacrolimus release from minicapsules of Example 1 (Format 1) coated with15% weight gain Eudragit™ RS30D followed by 25% weight gain Eudragit™FS30D: Dissolution profiles in FIG. 7 demonstrate the following releaseof tacolimus from minicapsules expressed as a percentage of the totalminicapsule content: less than 10% within 1 hr; less than 30% within 4hrs; less than 75% within 12 hrs and less than or equal to 100% at 24hr. This is suited either to a once-daily systemic absorption productor, more particularly, an ileum/colon-specific product.

Example 5

As per FIG. 2 above, Example 5 represents a controlled releaseliquid-filled minicapsule of the Format 2 variety. To develop asemi-solid or solid-filled capsule, the core formulation was prepared asfollows: Ovalbumin(OVA) was dissolved in a suitable volume of blendedLecithin and Saturated Triglycerides (Hard Fat—Witespol® H15), heatedand stirrer until in solution. The shell solution was prepared asfollows: Appropriate quantities of gelatine, sodium hydroxide, HP-55 andwater were mixed, stirred and heated to 70 degrees Celsius until insolution. The minicapsules were prepared using a Spherex Labo to produce2-layer minicapsules, the core of which comprises ovalbumin in solution.

TABLE 2 Oral Vaccine Formulation Formulation 1 Formulation of Water 82.5shell solution (Wt %) Gelatin 10.5 Glycerin 1.75 Chitosan 1.75 HP-553.15 NaoH 0.35 Formulation of Hard Fat 88 core solution (Wt %) Lecithin10 Ovalbumin 2

Ovalbumin (antigen) and Chitosan (adjuvant) is released from uncoatedminicapsules as follows: 0% released within 1 hour and 100% within 8hours.

Example 6

As per FIG. 2 above, Example 6 represents a controlled releaseliquid-filled minicapsule of the Format 2 variety. To develop asemi-solid or solid-filled capsule, the core formulation was prepared asfollows: Ovalbumin was mixed with Algel (Alum Adjuvant) and Poly I:C(Inosine: Cytosine) methylated—oligonucleotide, dissolved in a suitablevolume of blended Lecithin and Saturated Triglycerides (HardFat—Witespol® H15), heated and stirred until in solution. The shellsolution was prepared as follows: Appropriate quantities of gelatine,sodium hydroxide, HP-55 and water were mixed, stirred and heated to 70degrees Celsius until in solution. The minicapsules were prepared usinga Spherex Labo to produce 2-layer minicapsules, the core of whichcomprises ovalbumin in solution. To enable small intestinal and colonicdelivery the minicapsules were coated with 12.5% Surelease®. To enablemucoadhesion, the minicapsule shell contained chitosan.

TABLE 3 Oral Vaccine with Poly I:C and Alum as Adjuvants Formulation %w/w Formulation of Water 82.5 shell solution (Wt %) Gelatin 10.5Glycerin 1.75 Chitosan 1.75 HP-55 3.15 NaoH 0.35 Formulation of HardFat(a) 81.45 core solution (Wt %) Lecithin 9.05 Ovalbumin 1 Algel 7.5Poly I; C 1Ovalbumin (antigen) and Chitosan (adjuvant) is released from uncoatedminicapsules as follows: 0% released within 1 hour and 100% within 12hours.

Example 7

FIG. 8 represents the immune response in mice immunised withminicapsules as described in Example 5 and Example 6. Administration of100 μg ovalbumin with the adjuvant poly I:C in minicapsule formulationsinduces serum IgG responses. Mice were immunised on 3 consecutive dayson week 0 followed by an identical series of booster immunisations atweek 2. Serum samples were collected prior to the booster and one weekfollowing the booster and antigen specific IgG was assessed by ELISA.Immunisation with OVA or particularly OVA and poly I:C induced strongserum IgG responses after the initial series of immunisations andparticular after booster immunisation

Example 8

FIG. 9 represents the immune response in mice immunised withminicapsules as described in Example 5 and Example 6. Administration ofovalbumin in coated minicapsule formulations is more effective in theinduction of mucosal IgA (Immunoglobulin A) responses than the deliveryof OVA with the adjuvant poly I:C. Mice were immunised on 3 consecutivedays on week 0 followed by an identical series of booster immunisationsat week 2. Intestinal washes were collected one week following thebooster and antigen specific IgA and IgG was assessed by ELISA. Thisindicates that the protection of OVA from proteolysis by means ofminiencapsulation can enhance the induction of a mucosal IgA response.Mucosal antibody responses IgG In terms of the titres of antigenspecific IgG in the intestinal washes the highest responses weredetected in mice immunised with OVA in solution or OVA and poly I:C.

Example 9

FIG. 10 represents the immune response in mice immunised withminicapsules as described in Example 5 and Example 6. Immunisation withOVA, as per Examples 5 and 6, induced a strong antigen specific IFN-γproduction by spleen cells. Mice were immunised on 3 consecutive days onweek 0 followed by an identical series of booster immunisations at week2. Spleen cells were re-stimulated with antigen 7 days after the boosterimmunisation and IL-17 and IFN-γ concentrations were determined by ELISAafter 3 days. Enteric administration of OVA with chitosan induced astrong IFN-γ response on re-stimulation with antigen.

Example 10

FIG. 11 represents the immune response in mice immunised withminicapsules as described in Example 5 and Example 6. Immunisation withOVA, as per Examples 5 and 6, induced strong antigen specific IL-4 andIL-10 production by spleen cells. Mice were immunised on 3 consecutivedays on week 0 followed by an identical series of booster immunisationsat week 2. Spleen cells were restimulated with antigen 7 days after thebooster immunisation and IL-4, IL-5 and IL-10 concentrations weredetermined by ELISA after 3 days. Responses in mice immunised withuncoated minicapsules (Example 5) were weaker than in the case of thecoated minicapsules (Example 6) suggesting that the enteric coat on theparticles protected OVA such that more potent T cell responses wereinduced.

Example 11

FIG. 12 represents the immune response in mice immunised withminicapsules as described in Example 5 and Example 6. Immunisation withOVA in uncoated minicapsules (Example 5) induces strong antigen specificIFN-γ production by mesenteric lymph node cells. Mice were immunised on3 consecutive days on week 0 followed by an identical series of boosterimmunisations at week 2. Spleen cells were restimulated with antigen 7days after the booster immunisation and IL-17 and IFN-γ concentrationswere determined by ELISA after 3 days. The uncoated formulation (Example5) was more effective than the coated formulation (Example 6) in termsof inducing antigen specific T cells secreting IL-4, IL-5 and IFN-γ.

Example 12

As per FIG. 3 above, Example 12 a dispersion of micronized (ornanonized) drug, in this case micronized tacrolimus dispersed in a solidgelling agent and is representative of Format 3. The solid minicapsules(minispheres) were prepared as follows: Appropriate quantities ofmicronised tacrolimus, gelatine and sorbitol are added to water andheated to 80° C., continually stirring until in a homogeneous solution.The solution is then processed into solid minispheres at an appropriateflow rate and vibrational frequency. The resulting minispheres arecooled in oil. The cooled minispheres are harvested and centrifuged toremove residual oil and dried overnight.

TABLE 4 1-Layer Micronized Tacrolimus Minicapsules (Minispheres)Ingredients % w/w Core Composition Tacrolimus 2.5 (Micronised) Gelatin87.5 Sorbitol 9.7

To enable the development of a once-daily or an ileum- andcolon-specific product, the minicapsules are coated with a range ofsustained release polymers, namely differing weight gains of Surelease®,ranging from 0 to 30% weight gain, or variable weight gains ofSurelease® plus variable concentrations of pectin.

Example 13

Tacrolimus release from uncoated minicapsules, prepared as per Example12: Dissolution profiles in FIG. 13 demonstrate the following release oftacolimus from minicapsules expressed as a percentage of the totalminicapsule content: greater than 90% within 1 hr and less than or equalto 100% at 4 hrs.

Example 14

Tacrolimus release from minicapsules, prepared as per Example 12, coatedwith 10% weight gain Surelease®: Dissolution profiles in FIG. 14demonstrate the following release of tacolimus from minicapsulesexpressed as a percentage of the total minicapsule content: less than10% within 1 hr; less than 95% within 4 hrs and less than or equal to100% at 8 hr.

Example 15

Tacrolimus release from minicapsules, prepared as per Example 12, coatedwith 15% weight gain Surelease®: Dissolution profiles in FIG. 15demonstrate the following release of tacolimus from minicapsulesexpressed as a percentage of the total minicapsule content: less than10% within 1 hr; less than 25% within 4 hrs and less than or equal to100% at 8 hr.

Example 16

Tacrolimus release from minicapsules, prepared as per Example 12, coatedwith 20% weight gain Surelease®: Dissolution profiles in FIG. 16demonstrate the following release of tacolimus from minicapsulesexpressed as a percentage of the total minicapsule content: less than10% within 1 hr; less than 20% within 4 hrs and less than 95% within 8hrs and less than or equal to 100% at 12 hr.

Example 17

Tacrolimus release from minicapsules, prepared as per Example 12, coatedwith 25% weight gain Surelease®: Dissolution profiles in FIG. 17demonstrate the following release of tacolimus from minicapsulesexpressed as a percentage of the total minicapsule content: less than10% within 1 hr; less than 20% within 4 hrs and less than 70% within 8hrs; less than 95% within 12 hrs and less than or equal to 100% at 24hr.

Example 18

Tacrolimus release from minicapsules, prepared as per Example 12, coatedwith 30% weight gain Surelease®: Dissolution profiles in FIG. 18demonstrate the following release of tacolimus from minicapsulesexpressed as a percentage of the total minicapsule content: less than10% within 1 hr; less than 10% within 4 hrs and less than 30% within 8hrs; less than 90% within 12 hrs and less than or equal to 100% at 24hr.

Example 19

Tacrolimus release from minicapsules, prepared as per Example 12, coatedwith a range of Surelease® weight gains (0-30% weight gain): Dissolutionprofiles in FIG. 19 demonstrate the variable release of tacolimus fromminicapsules expressed as a percentage of the total minicapsule content.

Example 20

As per FIG. 3 above, Example 20 is an example of an extruded emulsiondrug suspension, in this case hydralazine and is representative ofFormat 4. Gelatine is mixed with water, heated to 65 degree C. andstirred until dissolved. Hydralazine is added to the heated gelatinesolution and the mixture until an homogenous solution (Solution 1).Squalene, Gelucire 44/14 and Labrifil MS 1944 CS is heated and mixeduntil in an homogenous solution (Solution 2). Solution 1 and Solution 2are then blended and homogenized to give an emulsified suspension. Theemulsified suspension is then, using a single nozzle minicapsuleprocessor or extruder to which a vibration force is applied, extrudedand cooled either in a cooling bath or in the air.

TABLE 5 Extruded Hydralazine emulsion suspension Ingredients Wt (g) CoreComposition Hydralazine 0.1 Gelatine 10 Water 40 Squalene 0.16 Gelucire44/14 0.16 Labrafil MS 1944 CS 0.8

The resulting spherical extruded beads had a content assay of 36 mg/gand a processing yield of over 90% efficiency. The beads are readilydissolved and may be coated to provide any desired release profile,

Example 21

Colitis was induced in mice using DSS 2.5% in drinking water. DMOGmini-capsules of example 20 with two different coating were used, namelyDSS-bead (0.25 mg—immediate release), and DSS-COAT-bead (DSS-COAT beadscoated with 22% Surelease®—DMOG: 0.25 mg/day) and were compared tonon-treated DSS-induced colitis mice and mice treated with 8 mg DMOG IPevery second day. The minicapsules were prepared using the methoddescribed in Example 20 above.

As DMOG is known to increase the production of erythropoietin it isexpected that in the presence of systemic DMOG that the packed cellvolume would be increased. The packed cell volume (PCV) is a measurementof the proportion of blood that is made up of cells. The value isexpressed as a percentage or fraction of cells in blood. The PCV riseswhen the number of red blood cells increases. FIG. 20 demonstrates that,on Day 7, when administered IP that DMOG increases the PCV, despite thefact that these mice exhibited a high DAI and that the DSS alone reducedthe PCV. It is noteworthy that neither the non-coated DSS DMOG beads orthe colon-specific coated DMOG beads did not increase the PCV, despitethe fact that the colon-specific coated DMOG beads improved the healthof the DSS treated mice and that these mice demonstrated improved DAI.Thus, it could be concluded that when administered within the intestinalor colonic lumen that it acts locally at low dose and negligibleconcentrations are systemically available.

Example 22

Referring to FIG. 21, the disease activity index (DAI) is calculated asthe sum of scores of weight loss, stool consistency and blood in feces.Normal stool=formed pellets; loose stool=pasty and semi-formed stoolwhich do not stick to the anus; diarrhoea=liquid stools that stick tothe anus. This composite scoring system clearly demonstrates that dailyadministration of DMOG specifically to the colon (DSS-COAT beads coatedwith 22% Surelease®—DMOG: 0.25 mg/day) 0.25 mg DMOG produces apronounced protective effect against the induction of colitis in DSStreated mice. The minicapsules were prepared using the method describedin Example 20 above.

Example 23

Referring to FIG. 22, following removal of the colon from mice on Day 7,it is observed that while the DSS still exerted a shortening affect onthe colon length, the administration of DMOG IP (8 mg DMOG every secondday) and colon-specific coated DMOG beads (DSS-COAT beads coated with22% Surelease®—DMOG: 0.25 mg/day) significantly reduced colonshortening, thereby suggesting that DMOG is exerting a protective effectagainst DSS-induced colitis. A major symptom of DSS-induced colitis isweight loss. From FIG. 21 it is evident that when administered IP(DSS-DMOG) every second day, 8 mg DMOG has a significant protectiveeffect compared with the non-treated mice (DSS). Likewise, when 0.25 mgDMOG is administered daily as colon-specific beads (DSS-COAT beadscoated with 22% Surelease®—DMOG: 0.25 mg/day), the protective effect ispronounced. The 0.25 mg DMOG, administered daily in an immediate releaseformat (DSS-bead) had a slight protective effect. This data set suggeststhat when administered specifically to the colon daily at lowconcentration; DMOG has a pronounced protective effect on DSS-inducedcolitis. The minicapsules were prepared using the method described inExample 20 above.

The invention is not limited to the embodiments hereinbefore describedwhich may be varied in detail.

The invention claimed is:
 1. An oral composition comprising minicapsuleswherein the minicapsules comprise an active pharmaceutical in a liquid,semi-solid or solid core, the minicapsules having release profiles torelease the active pharmaceutical in an active form in the colon and theminicapsules comprising a gelling agent encapsulating the activepharmaceutical selected from solubilised active pharmaceutical anddispersed active pharmaceutical, and combinations thereof, and theminicapsules being coated to target release to the colon, and the activepharmaceutical being selected from: an antigen with an adjuvant;antigenic, and optionally covalently or non-covalently modified,peptides, in combination with an adjuvant and/or permeability enhancer;activators of Nuclear Factor Kappa B (NFκB); a kappa B alpha (IKκBα)kinase inhibitor and/or covalent or non-covalent derivatives thereof;nicotine and/or derivatives thereof; a COX-II inhibitor; one or acombination of insulin sensitizers, sulphonamides, glucagon-likepeptides; TNFα inhibitors; NFκβ inhibitors; or a combination thereof. 2.The composition of claim 1, wherein the active pharmaceutical comprisessolubilised active pharmaceutical.
 3. The composition of claim 1,wherein the minicapsules are coated to target release in the colon. 4.The composition of claim 1, wherein the minicapsules further comprise anexcipient selected from an excipient to maximize permeability of theactive pharmaceutical compound(s) in the colon, an excipient to maximizesolubility of the active pharmaceutical compound(s) in the colon, andcombinations thereof.
 5. The composition of claim 1 wherein theminicapsules further comprise an excipient selected from sodium caprate,sodium dodecanoate, sodium palmitate, SNAC, chitosan and derivativesthereof, fatty acids, fatty acid esters, polyethers, bile salts,antioxidants, and nitric oxide donors, and combinations thereof.
 6. Thecomposition of claim 1 wherein the minicapsules are minicapsules inwhich the active pharmaceutical is as a solubilised formulationencapsulated with the gelling agent and have the characteristics ofminicapsules obtained by a process utilising surface tension ofdifferent solutions and comprising ejecting through a nozzle having asingle orifice a hydrophobic solution or suspension and a solutioncomprising the gelling agent, to form into a spherical form and fallinto a cooling air flow or into a cooling or hardening solution wherebythe gelling agent is gelled and encapsulates the hydrophobic suspensionor solution.
 7. The composition of claim 1 wherein the active issolubilised and the minicapsules are coated to target release to theileum and the colon.
 8. The composition of claim 1 wherein the active isas a hydrophobic solution.
 9. The composition of claim 1 wherein theminicapsules comprise an emulsion comprising the gelling agent whichemulsion is in extruded, gelled and dried form.
 10. The composition ofclaim 9 wherein the active pharmaceutical is solubilised in ahydrophobic solution and the minicapsules comprise gelatin as thegelling agent.
 11. The composition of claim 1 wherein the activepharmaceutical is protected from the environment of the uppergastrointestinal tract.
 12. The composition of claim 1 wherein theactive pharmaceutical is a COX-2 inhibitor.
 13. The composition of claim12, wherein the COX-2 inhibitor is celecoxib.
 14. The composition ofclaim 1 wherein the active pharmaceutical is in a solubilised liquid,semi-liquid or solid form.
 15. The composition of claim 1 wherein thegelling agent is modified to achieve modified release.
 16. Thecomposition of claim 1 wherein the minicapsules are coated with acoating selected from a modified release coating, and a controlledrelease coating comprising a material selected from acrylic-,methacrylic-, and ethylcellulose-based polymers and combinationsthereof.
 17. The composition of claim 1 wherein the minicapsules arecoated with a coating comprising a polymer-based matrix susceptible tobacterial breakdown by colonic bacteria.
 18. The composition of claim 1wherein the minicapsules comprise an extruded and gelled emulsion whichcomprises the active pharmaceutical and a medium chain triglyceride. 19.The composition of claim 1 wherein the minicapsules comprise an extrudedand gelled emulsion which comprises the active pharmaceutical and a longchain fatty acid.
 20. The composition of claim 18, wherein theminicapsules have a controlled release coating comprising a materialselected from acrylic-, methacrylic-, and ethylcellulose-based polymersand combinations thereof.
 21. The composition of claim 1 wherein theactive pharmaceutical comprises an insulin sensitizer, a sulphonamide, aglucagon-like peptide, or a combination thereof, and further comprisinginsulin.
 22. The composition of claim 21 wherein the insulin, insulinsensitizers, sulphonamides, and glucagon-like peptides are releasedconcomitantly or sequentially.
 23. The composition of claim 1, whereinthe release is a pH-independent release.
 24. The composition of claim 1wherein the active pharmaceutical is protected from the environment ofthe upper gastrointestinal tract but allows abrupt and/or sustainedrelease into the proximal colon.
 25. The composition of claim 1 whereinthe active pharmaceutical is solubilised and the minicapsules compriseminicapsules that are coated to permit targeted release in the colon orthe ileum.
 26. The composition of claim 1, which has a dissolutionprofile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C.and 50 rpm, in pH 6.8 buffer as follows: up to 4 hours: less than orequal to about 20% active pharmaceutical released.
 27. The compositionof claim 26 which has a dissolution profile, when tested in a U.S.P.Type II apparatus (paddles) at 37° C. and 50 rpm, in pH 6.8 buffer asfollows: 24 hours: from about 75% to about 100% active pharmaceuticalreleased.
 28. The composition of claim 1 which has a dissolutionprofile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C.and 50 rpm, in pH 6.8 buffer as follows: 1 hour: less than or equal toabout 20% active pharmaceutical released; 4 hours: less than or equal toabout 35% celecoxib released.
 29. The composition of claim 28 which hasa dissolution profile, when tested in a U.S.P. Type II apparatus(paddles) at 37° C. and 50 rpm, in pH 6.8 buffer as follows: 16 hours:about 75% active pharmaceutical released.
 30. An oral compositioncomprising minicapsules wherein the minicapsules comprise an activepharmaceutical in a liquid, semi-solid or solid core, the minicapsuleshaving release profiles to release the active pharmaceutical in anactive form in the colon, wherein the minicapsules comprise an emulsioncomprising gelatin and the core, which emulsion is in extruded, gelledand dried form, wherein the minicapsules are coated with a coatingselected from a modified release coating, and a controlled releasecoating, and the active pharmaceutical being selected from: an antigenwith an adjuvant; antigenic, and optionally covalently or non-covalentlymodified, peptides, in combination with an adjuvant and/or permeabilityenhancer; activators of Nuclear Factor Kappa B (NFκB); a kappa B alpha(IKκBα) kinase inhibitor and/or covalent or non-covalent derivativesthereof; nicotine and/or derivatives thereof; a COX-II inhibitor; one ora combination of insulin sensitizers, sulphonamides, glucagon-likepeptides; TNFα inhibitors; NFκβ inhibitors; or a combination thereof.31. The composition of claim 30, wherein the coating comprises amaterial selected from the group consisting of acrylic-, methacrylic-,and ethylcellulose-based polymers and combinations thereof.
 32. Thecomposition of claim 30 wherein the active pharmaceutical is in asolubilised liquid, semi-liquid or solid form.
 33. The composition ofclaim 30 wherein the active pharmaceutical is lipophilic and issolubilised in a hydrophobic solution.
 34. The composition of claim 33,wherein the minicapsules have a release profile to release in the colonan amount of the active pharmaceutical effective for managing thetreatment of colon associated inflammatory bowel disease without anyassociated dose related side-effects.
 35. The composition of claim 34,wherein the inflammatory bowel disease is selected from Crohn's Disease,Ulcerative Colitis and GI-Graft-Versus-Host Disease.
 36. The compositionof claim 1, wherein the active is in a solubilised liquid form.
 37. Thecomposition of claim 1, wherein the active is readily soluble in thegastrointestinal environment.
 38. The composition of claim 1 wherein thecoating comprises ethylcellulose.
 39. The composition of claim 1 that isadapted for administration to a human subject.
 40. A process ofpreparing minicapsules of claim 1, the process utilising surface tensionof different solutions and comprising ejecting through a nozzle having asingle orifice a hydrophobic solution or suspension and a solutioncomprising the gelling agent, to form into a spherical form and fallinto a cooling air flow or into a cooling or hardening solution wherebythe gelling agent is gelled and encapsulates the hydrophobic suspensionor solution.
 41. The process of claim 40, wherein the gelling agent isgelatin.
 42. The process of claim 40, which further comprises applyingone or more coating layers.
 43. A method for treating or preventingcarcinomas, polyps, and/or cysts of the colon and/or rectum, comprisingadministering an effective amount of the composition of claim 1 to apatient.
 44. The method of claim 43 wherein the active pharmaceutical isselected from a COX-2 inhibitor and an antimetabolite.
 45. The method ofclaim 43, wherein the patient is human.
 46. A method selected from amethod of reducing in a subject the number of colorectal polyps infamilial adenomatous polyposis (FAP) and a method for administration toa subject having FAP in the care of the subject, the method comprisingadministering to the subject the composition of claim
 13. 47. The methodof claim 46 which comprises said method for administration to a subjecthaving FAP in the care of the subject, and wherein said method comprisessurgery.
 48. The method of claim 46, wherein the subject is human. 49.The composition of claim 30, wherein the active is in a solubilisedform.
 50. The composition of claim 30 wherein the coating comprisesethylcellulose.
 51. The composition of claim 30 that is adapted foradministration to a human subject.